Skip to main content Accessibility help


  • Access
  • Cited by 52



      • Send article to Kindle

        To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Hypothalamic dysfunction in obesity
        Available formats

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Hypothalamic dysfunction in obesity
        Available formats

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Hypothalamic dysfunction in obesity
        Available formats
Export citation


A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-κB kinase subunit β/NK-κB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.


agouti-related peptide


arcuate nuclei


cocaine and amphetamine-regulated transcript


ciliary neurotrophic factor


endoplasmic reticulum


inhibitor of NF-κB kinase subunit β


c-Jun amino-terminal kinase




mammalian target of rapamycin


neuropeptide Y




reactive oxygen species


Toll-like receptor 4


unfolded protein response


white adipose tissue

The developed world is currently facing an epidemic of obesity. Diseases associated with obesity, particularly type 2 diabetes, CVD, cancer, stroke and mental health issues, including dementia( 1 , 2 ) are provoking a crisis in health care, adversely affecting health and life expectancy and increasing health care costs, estimated to be up to £45 billion by 2050 in the UK alone( 3 ). Direct and indirect costs of type 2 diabetes, for example, one of the major health consequences of obesity, are currently £21·8 billion and set to rise to £35·6 billion by 2035–36 in the UK( 4 ).

Obesity is the result of a disproportionately high energy intake compared to energy expenditure and is a complex interaction between environmental and genetic factors( 5 ) with monogenic defects being relatively rare( 6 ). It seems obvious that an energy-dense diet, high in saturated fat and sugar, should cause weight gain and increased adiposity; nonetheless it appears that these diets cause a profound change in energy balance that does not result from a simple increase in energetic intake. Diet composition, particularly the presence of long-chain saturated fats, results in metabolic dysfunction and increased adiposity and body weight, which is defended so that any subsequent weight loss through energetic restriction is difficult to maintain( 7 ).

It is well known that the hypothalamus regulates energy balance, carrying out this process by integrating peripheral hormonal and neuronal signals of satiety and nutritional status( 8 10 ), and by directly sensing nutrients( 11 , 12 ). The hypothalamus not only regulates food intake and energy expenditure but also the utilisation and partitioning of nutrients( 13 ), the regulation of glucose homoeostasis( 14 ) and peripheral lipid metabolism( 15 17 ). Two important anorexigenic hormones that signal adiposity and nutritional status to the hypothalamus and inhibit food intake are leptin, produced by white adipose tissue (WAT), and insulin, produced by the pancreatic β-cells. While circulating levels of leptin and insulin rise in obesity, insensitivity to both hormones rapidly develops making it a hallmark feature of obesity. In addition to the classical target tissues for insulin action, such as the liver, muscle and WAT, insulin also acts in the hypothalamus playing a pivotal role not only in maintaining energy balance but also in regulating peripheral lipid and glucose metabolism( 18 20 ). Leptin is not only a potent regulator of food intake and possibly energy expenditure( 21 ), but also acts in concert with the central action of insulin in the maintenance of peripheral glucose homoeostasis( 14 , 22 ). Ghrelin is the only peripheral orexigenic hormone. It is produced mainly in the stomach and acts in the hypothalamus to stimulate food intake and weight gain via increased adiposity( 23 ). It is released from the stomach immediately preceding meals in human subjects( 24 ) and is n-octanoylated to produce the form of ghrelin which is active in energy balance( 23 ). Ghrelin acts via its receptor GHS-R in the hypothalamus and, counter intuitively, insensitivity to ghrelin also develops in diet-induced obesity( 25 ).

The complexity of, and numerous levels of control over, energy balance in the hypothalamus begs the question as to how this system can be so easily compromised and degraded in obesity. A key factor in the obesity epidemic, and the cause of the hypothalamic failure to regulate energy balance, appears to be the availability of highly palatable, energy-dense foods high in saturated fats and refined sugars. In the USA, an increase in total energy intake has occurred, largely since the 1980s, which tracks with the increase in obesity indicating that food is a pivotal factor in the obesogenic environment( 26 ). Recently ‘over nutrition’ has been recognised as not just a contributory factor to obesity but also as a mechanistic link stimulating the innate immune system and causing an atypical inflammation that is fundamental in the development of obesity and metabolic disease. In human subjects, chronic systemic low grade inflammation is marked by an increase in inflammatory markers in the circulation, such as C-reactive protein, TNFα, IL-1 and IL-6 in obese individuals, although a considerable overlap in values can occur between lean and obese. Nevertheless, a correlation exists between high levels of inflammatory markers and increasing BMI( 27 ). Thus, it is now widely accepted that obesity is related to low levels of systemic inflammation( 28 , 29 ), and a new concept of immunometabolism has emerged recognising the close functional links between the two processes( 30 ). The most widely studied dietary components in the induction of inflammation are the long-chain SFA( 31 ).

It is only relatively recently that inflammation has also been shown to occur in the hypothalamus in obesity( 32 34 ). Indeed hypothalamic ‘injury’ has been identified in rodents on a high-fat diet as early as 1 d after the start of feeding( 35 ). The inflammation in the hypothalamus caused by diet differs from inflammation due to sickness( 36 ). In the sickness response, food intake is inhibited and body weight is lost mainly due to the energetic demands of sustaining an elevated temperature, whereas diet-induced hypothalamic inflammation results in obesity( 37 ). Thus, over nutrition must be able to cause inflammation via subtly different mechanisms compared to the sickness response. The role of over nutrition and its impact on the hypothalamus has taken centre stage as the causative mechanism in the development of obesity and metabolic dysfunction( 38 ). Part of this recognition has come from the identification of a number of processes elicited in the hypothalamus by diet, particularly the pro-inflammatory effects of a long-chain SFA and the role of lipid metabolism in the hypothalamus and its importance as a basic cellular mediator of energy regulation. Additionally the role of reactive oxygen species (ROS) in hypothalamic cellular signalling in energy balance( 39 , 40 ) and the effect of oxidative stress when ROS levels rise uncontrollably has been identified. Endoplasmic reticulum (ER) stress has also been shown to occur in the hypothalamus as well as in peripheral tissues in response to over nutrition( 41 ). Finally, the recognition that both neuronal and synaptic plasticity are integral to hypothalamic energy balance and that these processes involve the resident inflammatory and support cells of the brain, the microglia and the astrocytes, respectively, and that both cell types are involved in the inflammatory response to a high-fat diet( 42 45 ), has brought all of these processes together. In combination, they demonstrate that over nutrition can damage the neuronal substrate of energy balance at many levels ranging from the intracellular to the structure of key neuronal interactions, thus, contributing to obesity and metabolic dysfunction. Importantly these mechanisms are only now beginning to be characterised, and in doing so many potential drug targets may be revealed to combat obesity and related diseases. This review will bring together literature supporting the role of the hypothalamus as the key area for nutrient interaction in obesity and metabolic dysfunction. Stressors linking diet to hypothalamic dysfunction are also discussed. The object of the present review is to provide a summation of the processes involved in the interaction between a diet high in SFA and hypothalamic dysfunction. Many of the mechanisms described are complex and are in themselves the subject of recent review. Consequently, a detailed description of each separate process is beyond the scope of this review which aims to provide an overall picture of how diet can damage the hypothalamus.

Obesity, inflammation and insulin insensitivity

Cellular mechanisms

The fundamental links between obesity, inflammation and insulin insensitivity have been the subject of numerous research papers and reviews. Two main pro-inflammatory intracellular signalling mechanisms, the c-Jun amino-terminal kinase (JNK) 1 and inhibitor of NF-κB kinase subunit β (IKKβ)/NF-κB pathways, have been identified as being key in linking diet to metabolic dysfunction( 46 ). Both pathways are activated by metabolic stress and are causal in the induction of diet-induced obesity.

The JNK group of stress-activated kinases are part of the mitogen-activated protein kinase family and are stimulated by growth factors, pro-inflammatory cytokines, particularly TNFα, microbial factors, including lipopolysacccharide (LPS) and other stressors notably oxidative and ER stress( 47 ). The JNK are thought to increase inflammation by stabilising mRNA encoding pro-inflammatory cytokines and other mediators of inflammation( 46 48 ).

IKKβ is an integral part of the regulatory complex responsible for activation of the NF-κB inflammatory pathway, an important part of the innate immune response. IKKβ phosphorylates and inactivates the inhibitor of κB which prior to phosphorylation sequesters NF-κB in the cytoplasm. When freed NF-κB dimerises and enters the nucleus where it regulates transcription of a number of genes related to inflammation( 49 ). IKKβ is stimulated by pro-inflammatory cytokines, viruses and bacterial components, including LPS, and stressors such as oxidative and ER stress.

It has been known for some time that inflammation caused by infection and disease results in insulin insensitivity( 50 ) and that both diet-induced inflammation and insulin insensitivity can be reversed by anti-inflammatory agents such as salicylate( 51 , 52 ), demonstrating the connection between the two. Salicylate inhibits the activity of IKKβ( 53 ), which in addition to its role in inflammation also plays an important part in the insulin-signalling cascade( 46 ) inhibiting insulin receptor substrate 1 in adipocytes and hepatocytes( 54 ). IKKβ is also part of the mammalian target of rapamycin (mTOR)-Raptor complex( 55 ) and the mTOR pathway is part of a mechanistic link between insulin and leptin signalling( 56 ). mTOR also triggers ER stress and inhibits insulin signalling via JNK-mediated serine phosphorylation of insulin receptor substrate 1( 57 ). Stimulation of the IKKβ/NF-κB inflammatory pathway also induces SOCS3, an inhibitor of both leptin and insulin signalling( 33 ). JNK1 appears to act in the brain, particularly in the agouti-related peptide (AgRP) neurons to increase the inhibitory effects of insulin on food intake( 32 , 58 ), but under different conditions can have opposing effects on food intake and is proposed to be both a positive and a negative regulator of food intake( 58 ). Nonetheless, evidence indicates that it is the production of inflammatory cytokines via the IKKβ/NF-κB and JNK pathways that is the major link between inflammation and insulin insensitivity( 46 , 59 ).

White adipose tissue as a source of inflammation

Inflammation is normally a transient response to infection or injury and is rapidly resolved to prevent tissue damage and chronic disease( 60 ). However, in obesity although the inflammation is low grade it persists. Adipocytes are cells which not only store fat but also secrete a number of pro-inflammatory cytokines and adipokines in response to over nutrition and over expansion. This attracts monocytes into the tissue to become M1, pro-inflammatory, macrophages which form typical ‘crown-like’ structures surrounding necrotic and apoptotic adipocytes, releasing further pro-inflammatory cytokines( 61 , 62 ). The causes underlying the secretion of pro-inflammatory adipokines by WAT may be due to WAT over expansion causing hypoxia( 63 ) and/or high concentrations of NEFA being released through uncontrolled lipolysis due to insulin insensitivity in adipocytes( 64 ). However, dietary restriction in obese rodents has also been found to cause a rapid but transient influx of macrophages into WAT with a correlation between NEFA concentration and peak macrophage numbers, confirming the role of high concentrations of NEFA in this effect( 65 ). One of the pro-inflammatory cytokines released by WAT is TNFα. The concept that inflammation in WAT in obesity is causative in insulin insensitivity was first identified in rodent models of obesity where TNFα was elevated and both antibodies directed against TNFα and knockout of the TNFα gene prevented the induction of insulin insensitivity( 66 , 67 ). However, TNFα neutralisation in obese human subjects, while reducing the level of inflammatory markers, has no effect on insulin sensitivity( 68 ). Nonetheless the systemic inflammation in obesity due to the release of adipokines is still thought to be an important mechanism in metabolic dysfunction. However, in addition to the pro-inflammatory role of WAT pathways and mechanisms are still being uncovered which implicate diet directly with inflammation.

Food and inflammation

Nutrition can have an immediate effect on circulating markers of inflammation. Within hours of eating a fatty meal a transient increase in inflammatory markers is seen in the circulation. This reaction appears to be preferentially activated by TAG, SFA and glucose which trigger an acute innate response in circulating monocytes releasing TNFα and IL-6( 69 71 ). The most potent stimulator of the Toll-like receptor 4 (TLR4), the major signalling pathway in the innate immune response, is bacterial LPS or endotoxin. The potential for LPS, either ingested as a contaminant, particularly of highly processed food( 72 ), or from the gut microbiota entering the circulation after a high-fat meal has been demonstrated in rodent models of obesity( 73 ) and in human subjects( 74 ). Increased bodyweight, glycaemia and aging all increase the magnitude of the post-prandial inflammatory response indicating that the innate immune system is sensitised in these conditions( 27 ). Long-chain SFA have been shown to act as ligands for TLR4( 75 79 ) and mice that lack a functional form of this receptor are protected from obesity( 80 ) and from obesity-related insulin insensitivity( 81 ), administration of LPS has been shown to mimic the effects of a high-fat diet on adiposity and insulin insensitivity( 73 ). There is a possibility that dietary SFA act synergistically to amplify the response to LPS( 82 ) as transfected cells and cells naturally expressing TLR4 fail to respond to the fatty acids alone( 83 ). Whatever the ligands are that activate TLR4 its presence has been shown to be necessary for acute lipid-induced insulin insensitivity( 78 ).

The TLR4 response is dependent on the IKKβ/NF-κB pathway and IKKβ activation can also disrupt insulin signalling as detailed earlier( 84 ). Knockout of the genes encoding IKKβ and TLR4 in myeloid cells, which give rise to macrophages and neutrophils, protects mice from high-fat diet-induced insulin insensitivity in the muscle, fat and liver( 79 , 85 ). By contrast, IKKβ knockout in the liver protects only the liver( 85 ), indicating that the myeloid-derived cells of the immune system are necessary for diet-induced obesity and metabolic dysfunction. Deletion of JNK1, another key component of the inflammatory response stimulated via the TNFα receptor 1 also protects from obesity and insulin insensitivity( 86 ). In mice on a high-fat diet, insulin insensitivity mediated via TLR4 can be detected as early as 3 d after the start of diet, and hypothalamic inflammation after just 1 d, indicating that the diet rather than increased adiposity is the cause of insulin insensitivity and inflammation( 35 , 87 ). Both the IKKβ/NF-κB and the JNK pathways can also be stimulated via non-receptor stress mechanisms within the cell including oxidative stress, ER stress, and excess concentrations of ceramides all of which can be caused by excessive long-chain saturated fats in the diet( 46 , 88 ) (Fig. 1).

Fig. 1. (colour online) The major intracellular pathways involved in the induction of hypothalamic dysfunction are illustrated. All of these pathways interact with one another to amplify the response to a high-fat diet and obesity. Interactions between pathways are shown in both solid and dotted lines. Key: peroxisomes are shown in green and mitochondria in orange. ER, endoplasmic reticulium; IKKβ, inhibitor of nuclear factor κB kinase subunit β; JNK, c-Jun amino-terminal kinase; LCSFA, long-chain SFA; TLR4, Toll-like receptor 4; TNFR1, tumour necrosis factor receptor 1.

Hypothalamic control of energy balance

The hypothalamus contains several nuclei which play important roles in energy balance. The most important of these are the arcuate nuclei (ARC) which consist of groups of neurons within the mediobasal hypothalamus lying just above the median eminence and either side of the third ventricle (Fig. 2). Although other nuclei in the hypothalamus are inside the blood–brain barrier, the ARC lie, at least partially, outside and are perfectly placed to receive input from circulating hormones and nutrients and also from those in the cerebrospinal fluid present in the third ventricle.

Fig. 2. (colour online) The major neuronal cell types that control energy balance are part of the melanocortin system in the hypothalamus. They are mostly located in the arcuate and ventromedial nuclei. They are referred to as first-order neurons as they receive direct input from circulating hormones such as leptin, insulin and ghrelin. They then signal second-order neurons in areas such as the paraventricular nuclei. 3 V, third ventricle; AgRP, agouti-related peptide; αMSH, α melanocyte-stimulating hormone; CART, cocaine and amphetamine-regulated transcript; MC4R, melanocortin receptor 4; NPY, neuropeptide Y; POMC, proopiomelanocortin.

Two sets of neurons with opposing actions have been identified as being pre-eminent in energy balance regulation. One group of neurons stimulate appetite and are termed orexigenic and express neuropeptide Y (NPY) and AgRP, while the second group inhibit appetite and are termed anorexigenic and express proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART). Both sets of neurons possess the long signalling form of the leptin receptor, Ob-Rb, and leptin acts to inhibit the AgRP/NPY neurons while activating the POMC/CART neurons. These effects are seen at the level of both gene transcription and membrane polarisation( 89 ). Projections from the ARC reach the paraventricular nuclei which contain high levels of the melanocortin receptors 3 and 4. The melanocortin receptor 4 is the key receptor in energy balance with mutations of this receptor being the most frequent seen in human obesity( 90 ). POMC-derived α melanocyte-stimulating hormone acts as an agonist at these receptors and AgRP as an antagonist( 91 ), providing a dynamic balance to regulate energy balance. AgRP, the POMC gene and its product α melanocyte-stimulating hormone and the melanocortin receptors 3 and 4 are part of the central melanocortin system( 91 ).

Synaptic plasticity

The AgRP/NPY neurons contain GABA, an inhibitory neurotransmitter( 92 ). POMC/CART and AgRP/NPY neurons interact directly with one another in energy balance, with the AgRP neurons maintaining a tonic inhibitory effect on the anorexigenic POMC/CART neurons, via γ-aminobutyric acid, resulting in a stimulation of feeding. It has recently been shown that POMC/CART neurons can also directly inhibit AgRP/NPY. The balance of the interaction between these two neuronal types is dependent on synaptic plasticity. Although it has been known for some time that synaptic plasticity in the hypothalamus is important in osmotic regulation, reproductive behaviour and circadian rhythmicity( 93 ), its role in energy balance has only recently begun to be explored. Detailed analysis of the neurons in the ARC, particularly those of the melanocortin system, has been conducted in transgenic mice with NPY and POMC cells labelled with green fluorescent protein and visualised using fluorescence and electron microscopy. Both leptin and ghrelin have been shown to regulate the connectivity between AgRP/NPY and POMC/CART neurons in the ARC( 42 ) with astrocytes playing a pivotal role in this process by surrounding and ensheathing neurons and their processes and regulating synaptic input( 93 ).

The complex nature of the synaptic plasticity mediating the effects of both ghrelin and leptin has been recently demonstrated. In response to fasting, and an increase in circulating levels of ghrelin, a persistent up-regulation of an, as yet unidentified, excitatory synaptic input to AgRP neurons was observed. This presynaptic pathway releases glutamate that stimulates the AMPA receptor. This induces a positive feedback loop with AMP-activated kinase, mediating Ca release which activates the AgRP neuron and stimulates feeding behaviour. This process, including increased synaptic connectivity, is long lasting and self-sustaining which means that a transient ghrelin signal can sustain a long lasting increase in feeding behaviour. An increase in circulating leptin arrests this activity by stimulating POMC neurons to release the opioid neurotransmitter, β-endorphin, which switches off the AMP-activated kinase pathway, AgRP activity and feeding behaviour( 44 ) (Fig. 3).

Fig. 3. (colour online) Synaptic plasticity is important in the maintenance of energy balance in addition to direct input from peripheral hormones such as leptin, insulin and ghrelin. This figure illustrates how the two major energy balance neuronal types in the hypothalamus interact with one another via synaptic inputs which are largely inhibitory. AgRP, agouti-related peptide; CART, cocaine and amphetamine-regulated transcript; GABA, γ-aminobutyric acid; NPY, neuropeptide Y; POMC, proopiomelanocortin.

Synaptic organisation of the melanocortin system in rats resistant to diet-induced obesity compared with those vulnerable to diet-induced obesity differed in both the quantitative and qualitative synapses on POMC neurons. Ensheathment of POMC neurons by glial cells plays a key role in the process. In addition, the reactive gliosis observed on a high-fat diet (detailed later) results in restricted access of both POMC and NPY neuronal bodies and dendrites to the blood vessels( 94 ). Astrocytes are the most numerous cells in the brain and play roles intrinsic to its function, particularly synaptic plasticity. Microglia are the resident immune cells in the central nervous system and when activated they profoundly change their morphology, release cytokines and pro-inflammatory factors that may be neurotoxic( 95 ). In the hypothalamus, both astrocytes and microglia have been shown to be activated by a high-fat diet to the extent that after 1 week on the diet they form a reactive gliosis, normally seen after brain insult such as ischaemia or excitotoxicity( 35 ). This diet-induced gliosis resolves but returns later when obesity has more fully developed. Importantly it has been shown to occur in the hypothalamus of obese human subjects demonstrating that the changes observed in the diet-induced rodent hold true in human obesity( 35 ). Thus, hypothalamic inflammation can impinge on synaptic plasticity, an important mechanism in the regulation of energy balance.

Neuronal plasticity

It has been known for some time that treatment with ciliary neurotrophic factor (CNTF) can lead to weight loss( 96 , 97 ) and that its potent action continues for some time after treatment has been terminated( 98 ). CNTF shares common signalling pathways and anatomical localisation of receptors in the hypothalamus with leptin, but unlike leptin it can act in high-fat diet-induced obese rodents, which are leptin insensitive, and in db/db mice which lack functional leptin receptors( 99 , 100 ). CNTF is known to support neuronal survival both in vivo and in vitro ( 101 ) and has been shown to increase neurogenesis in the adult mouse hypothalamus which is intrinsically linked to the effect of CNTF in weight loss, as anti-mitotic agents can obliterate the effects of CNTF( 97 ). This strongly indicates a role for neurogenesis in the hypothalamic regulation of energy balance( 97 ). Up until this point very little attention had been paid to the potential role of neurogenesis in the adult hypothalamus, which had only been reported in two studies( 102 , 103 ). By using central instead of peripheral administration of bromodeoxyuridine, which is incorporated into replicating DNA, a much higher rate of neurogenesis has been found throughout the hypothalamus( 104 ). As neurogenesis occurs in the hypothalamus, then neuronal turnover and apoptosis must also take place to maintain the constant size of the hypothalamus. As a high-fat diet has been shown to induce inflammation in the hypothalamus and the mechanisms underlying inflammation and apoptosis are related, sharing common signalling pathways( 105 , 106 ), the rate of apoptosis was studied in the hypothalamus of both rats and mice on a high-fat diet( 107 ). The expression of a number of key pro-apoptotic genes was increased and the TUNEL assay showed increased numbers of apoptotic cells in the ARC and in the lateral hypothalamus, the majority of which were neurons( 107 ). When both measures of neurogenesis and apoptosis were integrated, a surprisingly large amount of neuronal remodelling of energy balance centres was demonstrated in adult rodents( 43 ). A high-fat diet both suppressed adult neurogenesis by increasing apoptosis in newly divided cells and depleted the number of proliferating progenitor glial cells, resulting in mice retaining older neurons while younger neurons underwent apoptosis( 43 ). The origin of this neurogenesis was identified as being the tanocytes, a specialised type of microglia, lining the base of the third ventricle in the median eminence( 108 ).

Hypothalamic fatty acid metabolism

SFA increase inflammation and insulin insensitivity in a number of cells and tissues. The role of NEFA in the induction of insulin insensitivity in peripheral tissues is a widely accepted concept( 109 , 110 ). However, recent evidence indicates that insulin insensitivity may not be directly related to the concentration of circulating NEFA( 111 ) and that the accumulation of diacylglycerol in peripheral tissues can induce insulin insensitivity in the absence of inflammation( 112 ). The ectopic accumulation of lipids in peripheral tissues and its effects on insulin sensitivity is termed lipotoxicity( 113 ).

It had been thought that NEFA were not normally used by the brain as an energy source and did not enter the brain. Recently, however, the uptake of fatty acids by the brain has been demonstrated using stable isotopes and positron emission tomography and was found to be increased in individuals with the metabolic syndrome and to subsequently decline after weight loss( 114 ). Apart from the use of lipids as an energy source in the brain it has become increasingly apparent that lipids and lipid metabolism play an important role in the regulation of energy balance by the hypothalamus. Circulating TAG have been shown to inhibit food intake by regulating the level of orexigenic peptides in the hypothalamus( 115 ) and long-chain SFA administered directly to the hypothalamus were shown to inhibit food intake( 116 ) demonstrating the role of lipids in the hypothalamic sensing of nutrient overload.

The more extensive role of fatty acid metabolism in the hypothalamic regulation of energy balance was first indicated by the inhibition of food intake by the central administration of C75, a fatty acid synthase inhibitor( 117 ). All of the enzymes of the fatty acid synthesis pathway are expressed in the ventromedial nuclei of the hypothalamus. These include acetyl-CoA carboxylase, fatty acid synthase and malonyl-CoA decarboxylase( 118 , 119 ). Additionally, it has been demonstrated that nutritional status regulates hypothalamic malonyl-CoA levels and fatty acid synthase expression in a nucleus-specific manner, with fatty acid synthase and acetyl-CoA carboxylase levels down-regulated by fasting and up-regulated by refeeding( 119 ). The extensive role of lipid metabolism in the hypothalamus has recently been revealed in mediating responses to both fasting( 120 ) and peripheral hormones, particularly ghrelin( 119 , 121 , 122 ), with elevation of the long-chain fatty acyl Co-A in the ARC decreasing food intake and whole body glucose metabolism( 19 ).

The AgRP/NPY neuron is important in stimulating feeding behaviour and is activated in response to fasting( 123 , 124 ), with ghrelin stimulating feeding behaviour by stimulating AgRP/NPY neurons to suppress POMC/CART neurons( 125 , 126 ). However, in fasting, circulating levels of glucose may be low and AgRP/NPY neurons have been shown to take up fatty acids from the circulation, which are raised in fasting due to lipolysis of WAT, and convert them to TAG for storage as cellular lipid droplets which are then metabolised via autophagy( 120 ). This is also seen as a process by which the neurons can protect themselves from the presence of NEFA. When autophagy is blocked specifically in AgRP/NPY neurons, mice are leaner and weigh less even when food is readily available, indicating that autophagy in these neurons is necessary for AgRP to stimulate feeding( 120 ). When autophagy is specifically blocked in POMC neurons, leptin signalling is inhibited and mice have increased body and fat mass( 127 ). However, when autophagy in the mediabasal hypothalamus as a whole is blocked by short hairpin RNA, the IKKβ/NF-κB pathway is stimulated and obesity results( 128 ). Thus, lipid biosynthesis and utilisation via autophagy in neurons in the hypothalamus are necessary for regulation of energy balance.

Hypothalamic inflammation and insulin insensitivity have been linked to the accumulation of the saturated long-chain palmitoyl- and stearoyl-CoA( 34 ), implicating lipids in the induction of inflammation in the hypothalamus. However, lipids are normally metabolised by the astrocytes which supply the neurons with ketone bodies particularly during suckling and starvation when lipids are the main energy supply( 129 ). Thus, these saturated long-chain acyl Co-A may only be present in quantity in astrocytes. Recently, it has been shown in rats that TLR4 stimulation is an upstream signalling event in SFA-induced ceramide biosynthesis in skeletal muscle, liver and hypothalamus, and that insulin insensitivity mediated via the TLR4 requires the biosynthesis of SFA-induced ceramide in liver and muscle. Nonetheless, blocking the biosynthesis of ceramide did not block the increase in SFA-stimulated circulating cytokine levels via TLR4( 130 ). Conversely, LPS also causes an increase in cellular ceramide levels and blocking the rise in ceramide effectively negates the influence of LPS on insulin sensitivity. It has been suggested that hypothalamic lipotoxicity could be an important link between a high-fat diet and neuronal dysfunction( 131 ). Hypothalamic lipidomics has the potential to identify changes in lipid species and metabolism in the hypothalamus in response to a diet high in saturated fat. Interestingly, high-fat diet-induced obesity can be reversed when saturated fat is replaced by unsaturated fat. This included an improvement of hypothalamic inflammation and the restoration of leptin and insulin sensitivity( 132 ).

Hypothalamic autophagy

Apart from a role in lipid metabolism, detailed earlier, autophagy is considered important in the general ‘housekeeping’ of the cell, removing damaged organelles and cytoplasm which is particularly relevant in metabolic stress( 133 ). Autophagy is an important response to cellular stress, particularly ER and oxidative stress, both of which are induced by over nutrition( 134 , 135 ). However, if cellular stressors continue over long periods then what is known as the autophagy defect occurs, which effectively negates the ability of the cell to remove damage. The autophagy defect can also activate the IKKβ/NF-κB pathway( 136 ). Recently the importance of autophagy in the hypothalamus was revealed by specific mediobasal hypothalamic knockout of a key gene, Atg7, in autophagy. Mice with this defect ate more and gained weight and showed hypothalamic activation of the IKKβ/NF-κB pathway. The effect of defective autophagy was reversed by inhibition of IKKβ( 128 ), clearly linking defective autophagy to hypothalamic inflammation.

Hypothalamic oxidative stress

The human brain represents approximately 2 % of the body weight, but accounts for around 20 % of the oxygen and energies consumed by the body( 137 ). This high rate of metabolism results in a susceptibility to oxidative stress( 138 ). Indeed oxidative stress is a key feature of many neurodegenerative diseases( 139 ). Mitochondria generate super oxide anions and hydrogen peroxide (O2 and H2O2), ROS, as by-products of energy generation. Usually the production and clearance of ROS, by antioxidant enzymes, is balanced between the mitochondria and peroxisomes, and plays an important role in cellular functions. Nonetheless persistent ROS can cause protein, lipid and DNA peroxidation and damage. Oxidative stress has been reported to precede the appearance of insulin insensitivity in high-fat diet-induced obesity( 140 ). The induction of hypertryglyceridaemia in rats has been shown to increase mitochondrial respiration in the hypothalamus together with an increase in ROS production( 141 ). ROS have been shown to be important in both glucose and lipid sensing by the hypothalamus( 141 , 142 ) and increased ROS in the hypothalamus of the Zucker fatty rat has been linked to abnormal glucose sensing( 143 ). Indeed in the hypothalamus, the regulation of the melanocortin system requires the presence ROS as an acute activator of firing by POMC neurons resulting in decreased food intake, and suppression of ROS leads to activation of the AgRP/NPY neurons and increased feeding. In lean mice, hypothalamic ROS is positively correlated with leptin levels, but levels drop after a high-fat diet as PPARγ is up-regulated together with the related increase in peroxisomes which act as ROS scavengers( 144 ). This decrease in ROS increases food intake and may be a mechanism by which hypothalamic leptin insensitivity is induced( 39 ). The recent finding that certain neurons utilise intracellular lipid as a source of energy during fasting and the fact that β oxidation of fatty acids promotes the generation of ROS( 145 , 146 ) demonstrates the potential for diets high in saturated fat to impact on hypothalamic fatty acid metabolism and oxidative stress and alter ROS signalling in the hypothalamus.

Hypothalamic endoplasmic reticulum stress

The cellular ER produces proteins for secretion and for intracellular function, and when stressed initiates a complex adaptive signalling response also known as the unfolded protein response (UPR). This process enables the cell to regulate the abundance of ER to fulfil its requirements for protein synthesis( 147 ). When the UPR continues uncontrolled it can lead to apoptosis and cell death as in the case of type 2 diabetes where increasing demands are placed on the pancreatic β-cells to produce insulin and the UPR eventually leads to pancreatic β-cell death( 148 ). The UPR in the liver has been shown to interfere with both insulin signalling and to promote weight gain( 29 ) with ER stress seen as a critical intracellular event that appears to link over nutrition to metabolic dysfunction( 149 , 150 ). The UPR regulates the expression of genes that encode chaperones, which help proteins to fold correctly but also stimulates the IKKβ/NF-κB and JNK inflammatory pathways. The UPR can be stimulated by a number of metabolic stressors including high levels of protein synthesis, high concentrations of glucose, starvation, hypoxia and elevated intracellular lipids( 151 ). In the hypothalamus, the UPR results from a high-fat diet and has been shown to be both a cause and a consequence of the NF-κB inflammatory pathway( 33 ). ER stress is also causative in the inhibition of leptin and insulin signalling via induction of PTP1B( 152 ). Central administration of drugs that induce ER stress recapitulate the effects of a high-fat diet on the IKKβ/NF-κB pathway( 33 ) and ER chaperones which reverse the UPR when delivered centrally reduce food intake and weight gain( 33 ).

Hypothalamic inflammation

Hypothalamic dysfunction is pivotal in the development of obesity and peripheral insulin insensitivity. Sensitivity to the circulating anorexigenic hormones, leptin and insulin, and the orexigenic hormone, ghrelin, is lost early in diet-induced obesity and high-fat feeding( 25 , 153 , 154 ). Insulin and leptin signalling in the hypothalamus are integrated via the phosphatidylinositol 3-OH kinase( 155 , 156 ), forkhead box protein O1( 157 , 158 ) and the mTOR pathways( 56 ). There also appear to be at least two inhibitors which target both insulin and leptin signalling; SOCS3( 159 , 160 ) and PTP1B( 161 ) with all of these pathways implicated in the induction of diet-induced leptin and insulin insensitivity.

While the role of obesity-related inflammation has been recognised in many peripheral tissues particularly WAT and liver, the role of inflammation in the hypothalamus has taken longer time to develop. Lack of response to the anorexic effects of insulin in the hypothalamus together with up regulation of JNK by a Western diet was noted in rats after just 10 d( 162 ) and has been recently shown to occur within 1–3 d of high-fat diet, but temporarily diminished to return permanently as obesity progressed( 35 ). Activation of inflammatory pathways in the hypothalamus of rats after 16 weeks on a high-fat diet has also been identified using macroarrays with an up-regulation of the inflammatory cytokines TNFα, IL-1β and IL-6, and inflammatory response proteins. These changes were correlated with the inability of an insulin challenge to inhibit food intake or to invoke a number of key steps in the insulin signalling pathway in the hypothalamus( 32 ). Blocking the inflammatory pathway in the hypothalamus with a specific inhibitor of JNK lowered adipose weight gain on the high-fat diet and preserved insulin signalling pathways. Pair-feeding experiments demonstrated that the effects of the JNK inhibitor were not due to the reduction in food intake. Leptin insensitivity in these animals, however, could not be reversed by the JNK inhibitor( 32 ). When central inflammation was induced by administration of TNFα, a known activator of JNK, it surprisingly decreased food intake and increased energy expenditure, but when given at lower doses it partially but significantly inhibited the anorexigenic actions of both leptin and insulin( 163 ). Inflammation, via TNFα, has also been shown to raise the levels of hypothalamic PTP1B, a major negative regulator of insulin and leptin sensitivity( 164 166 ).

Maintaining sensitivity to leptin depends on the prevention of diet induced ER stress( 167 ) and IKKβ activity( 33 ). Neuron-specific knockout of myD88, an adaptor protein that couples stimulation of the TLR and the IL-1 receptor to downstream intracellular events, protects mice from central obesity and both leptin and insulin insensitivity( 168 ). The hypothalamus expresses IKKβ at relatively high levels and when exposed to dietary or genetic obesity or nutrient stimulation (e.g. glucose or lipid), IKKβ is activated( 33 ). Pharmacological activation of the IKKβ/NF-κB pathway or introduction of constitutively active IKKβ causes obesity and leptin and insulin insensitivity while inhibition of the NF-κB pathway maintains leptin and insulin sensitivity and protects against obesity( 33 ). However, stimulation of this inflammatory pathway was not found to increase expression of hypothalamic cytokines( 33 ).

Microglia, the resident macrophages in the brain, are the major cells that express TLR4 and thus are the LPS responsive cells in the hypothalamus( 169 ). Confirming this, isolated neurons do not respond directly to long-chain SFA by increased inflammation or insulin insensitivity( 170 ) indicating that an indirect mechanism involving non-neuronal cells, almost certainly the microglia, is involved. Nonetheless, prolonged exposure of neurons to SFA does cause ER stress and apoptosis although the mechanism was not identified( 170 , 171 ). In the hypothalamus, both astrocytes and microglia have been shown to be activated by a high-fat diet( 35 ) indicating that both synaptic and neuronal plasticity, recently identified key mechanisms in energy balance, are almost certainly compromised.


The hypothalamic regulation of energy balance is rapidly and severely compromised by over nutrition, particularly on a diet high in saturated fat, which induces inflammation involving both the IKKβ/NF-κB and JNK inflammatory pathways coupled with oxidative and ER stress and the autophagy defect. All of these pathways and processes are interlinked and can be considered causal in the loss of central insulin and leptin signalling, and a prerequisite for the development of obesity. Also, the hypothalamus is a highly plastic tissue undergoing constant neuronal and synaptic remodelling in response to nutrient and hormonal signalling with astrocytes and microglia playing important roles in these processes. In response to obesity and a high-fat diet, a reactive gliosis occurs compromising the structure and the function of the hypothalamus. The paradox of how diet-induced hypothalamic inflammation results in obesity while the sickness-induced inflammation results in anorexia, even though the same inflammatory pathways are the basis for both, must surely depend on the nutritional background and the role of lipids in hypothalamic neuronal signalling.


I would like to thank Pat Bain (RINH) for graphics. The author declares no conflicts of interest. Work in the authors laboratory was funded the Scottish Government's Rural and Environment Science and Analytical Services Division and by a grant from the European Nutrigenomics Organisation funded by the EU Framework 6.


1. Brown, WV, Fujioka, K, Wilson, PW et al. (2009) Obesity: why be concerned? Am J Med 122, S4–S11.
2. Luchsinger, JA & Gustafson, DR (2009) Adiposity, type 2 diabetes, and Alzheimer's disease. J Alzheimers Dis 16, 693704.
3. Butland, B, Jebb, S, Kopelman, P et al. (2007) Tackling Obesities: Future Choices – Foresight Project Report, 2nd edition. Government Office for Science.
4. Hex, N, Bartlett, C, Wright, D et al. (2012) Estimating the current and future costs of type 1 and type 2 diabetes in the United Kingdom, including direct health costs and indirect societal and productivity costs. Diabetes Medicine 29, 855862.
5. Galgani, J & Ravussin, E (2008) Energy metabolism, fuel selection and body weight regulation. Int J Obes 32, S109S119.
6. Farooqi, IS & O'Rahilly, S (2007) Genetic factors in human obesity. Obes Rev 8 3740.
7. Velloso, LA & Schwartz, MW (2011) Altered hypothalamic function in diet-induced obesity. Int J Obes 35, 14551465.
8. Wynne, K, Stanley, S, McGowan, B et al. (2005) Appetite control. J Endocrinol 184, 291318.
9. Berthoud, HR (2002) Multiple neural systems controlling food intake and body weight. Neurosci Biobehav Rev 26, 393428.
10. Lopez, M, Tovar, S, Vazquez, MJ et al. (2007) Peripheral tissue-brain interactions in the regulation of food intake. Proc Nutr Soc 66, 131155.
11. Lam, TK, Schwartz, GJ & Rossetti, L (2005) Hypothalamic sensing of fatty acids. Nat Neurosci 8, 579584.
12. Blouet, C & Schwartz, GJ (2010) Hypothalamic nutrient sensing in the control of energy homeostasis. Behav Brain Res 209, 112.
13. Dieguez, C, Vazquez, MJ, Romero, A et al. (2011) Hypothalamic control of lipid metabolism: focus on leptin, ghrelin and melanocortins. Neuroendocrinology 94, 111.
14. Koch, C, Augustine, RA, Steger, J et al. (2010) Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. J Neurosci 30, 1618016187.
15. Nogueiras, R, Wiedmer, P, Perez-Tilve, D et al. (2007) The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest 117, 34753488.
16. Perez-Tilve, D, Hofmann, SM, Basford, J et al. (2010) Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nat Neurosci 13, 877882.
17. Bruinstroop, E, Pei, L, Ackermans, MT et al. (2012) Hypothalamic neuropeptide Y (NPY) controls hepatic VLDL-triglyceride secretion in rats via the sympathetic nervous system. Diabetes 61, 10431050.
18. Koch, L, Wunderlich, FT, Seibler, J et al. (2008) Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest 118, 21322147.
19. Obici, S, Feng, Z, Arduini, A et al. (2003) Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 9, 756761.
20. Lam, TK, Gutierrez-Juarez, R, Pocai, A et al. (2005) Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309, 943947.
21. Farooqi, IS & O'Rahilly, S (2009) Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr 89, 980S984S.
22. Berglund, ED, Vianna, CR, Donato, J Jr. et al. (2012) Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest 122, 10001009.
23. Nogueiras, R, Williams, LM & Dieguez, C (2010) Ghrelin: new molecular pathways modulating appetite and adiposity. Obes Facts 3, 285292.
24. Cummings, DE (2006) Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav 89, 7184.
25. Briggs, DI, Enriori, PJ, Lemus, MB et al. (2010) Diet-induced obesity causes ghrelin resistance in arcuate AgRP/NPY neurons. Endocrinol 151, 47454755.
26. Jeffery, RW & Harnack, LJ (2007) Evidence implicating eating as a primary driver for the obesity epidemic. Diabetes 56, 26732676.
27. Calder, PC, Ahluwalia, N, Brouns, F et al. (2011) Dietary factors and low-grade inflammation in relation to overweight and obesity. Br J Nutr 106, S5S78.
28. Kolb, H & Mandrup-Poulsen, T (2010) The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation. Diabetologia 53, 1020.
29. Hotamisligil, GS (2006) Inflammation and metabolic disorders. Nature 44, 860867.
30. Mathis, D & Shoelson, SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11, 81.
31. Fessler, MB, Rudel, LL & Brown, JM (2009) Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol 20, 379385.
32. de Souza, CT, Araujo, EP, Bordin, S et al. (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinol 146, 41924199.
33. Zhang, X, Zhang, G, Zhang, H et al. (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 6173.
34. Posey, KA, Clegg, DJ, Printz, RL et al. (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol 296, E1003E1012.
35. Thaler, JP, Yi, CX, Schur, EA et al. (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122, 153162.
36. Wisse, BE, Ogimoto, K, Tang, J et al. (2007) Evidence that lipopolysaccharide-induced anorexia depends upon central, rather than peripheral, inflammatory signals. Endocrinology 148, 52305237.
37. Thaler, JP, Choi, SJ, Schwartz, MW et al. (2010) Hypothalamic inflammation and energy homeostasis: resolving the paradox. Front Neuroendocrinol 31, 7984.
38. Cai, D & Liu, T (2012) Inflammatory cause of metabolic syndrome via brain stress and NF-kappaB. Aging 4, 98–115.
39. Diano, S, Liu, ZW, Jeong, JK et al. (2011) Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat Med 17, 11211127.
40. Andrews, ZB, Liu, ZW, Walllingford, N et al. (2008) UCP2 mediates ghrelin's action on AgRP/NPY neurons by lowering free radicals. Nature 454, 846851.
41. Yang, L & Hotamisligil, GS (2008) Stressing the brain, fattening the body. Cell 135, 2022.
42. Pinto, S, Roseberry, AG, Liu, H et al. (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110115.
43. McNay, DE, Briancon, N, Kokoeva, MV et al. (2012) Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. J Clin Invest 122, 142152.
44. Yang, Y, Atasoy, D, Su, HH et al. (2011) Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992–1003.
45. Thaler, JP, Yi, C-X, Hwang, BH et al. (2010) Rapid onset of hypothalamic inflammation reactive gliosis and microglial accumulation during high-fat diet-induced obesity. Endocrine Rev 32, OR33-1.
46. Solinas, G & Karin, M (2010) JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J 24, 25962611.
47. Chen, CY, Gherzi, R, Andersen, JS et al. (2000) Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation. Genes Dev 14, 12361248.
48. Chen, CY, Del Gatto-Konczak, F, Wu, Z et al. (1998) Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway. Science 280, 19451949.
49. Hayden, MS & Ghosh, S (2008) Shared principles in NF-kappaB signaling. Cell 132, 344362.
50. Chiolero, R, Revelly, JP & Tappy, L (1997) Energy metabolism in sepsis and injury. Nutrition 13, 45S51S.
51. Williamson, RT (1901) On the treatment of glycosuria and diabetes mellitus with sodium Salicylate. Br Med J 1, 760762.
52. Reid, J, MacDougall, AI & Andrews, MM (1957) Aspirin and diabetes mellitus. Br Med J 2, 10711074.
53. Kim, JK, Kim, YJ, Fillmore, JJ et al. (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108, 437446.
54. Hotamisligil, GS (2006) Inflammation and metabolic disorders. Nature 444, 860867.
55. Lee, DF, Kuo, HP, Chen, CT et al. (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440455.
56. Cota, D, Proulx, K, Smith, KA et al. (2006) Hypothalamic mTOR signaling regulates food intake. Science 312, 927930.
57. Ozcan, U, Ozcan, L, Yilmaz, E et al. (2008) Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29, 541551.
58. Unger, EK, Piper, ML, Olofsson, LE et al. (2010) Functional role of c-Jun-N-terminal kinase in feeding regulation. Endocrinol 151, 671682.
59. Cai, D, Yuan, M, Frantz, DF et al. (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11, 183190.
60. Serhan, CN, Brain, SD, Buckley, CD et al. (2007) Resolution of inflammation: state of the art, definitions and terms. FASEB J 21, 325332.
61. Xu, H, Barnes, GT, Yang, Q et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112, 18211830.
62. Apovian, CM, Bigornia, S, Mott, M et al. (2008) Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arterioscler Thromb Vasc Biol 28, 16541659.
63. Wood, IS, de Heredia, FP, Wang, B et al. (2009) Cellular hypoxia and adipose tissue dysfunction in obesity. Proc Nutr Soc 68, 370377.
64. Sanyal, AJ, Campbell-Sargent, C, Mirshahi, F et al. (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120, 11831192.
65. Kosteli, A, Sugaru, E, Haemmerle, G et al. (2010) Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J Clin Invest 120, 34663479.
66. Uysal, KT, Wiesbrock, SM, Marino, MW et al. (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610614.
67. Hotamisligil, GS, Shargill, NS & Spiegelman, BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 8791.
68. Bernstein, LE, Berry, J, Kim, S et al. (2006) Effects of etanercept in patients with the metabolic syndrome. Arch Intern Med 166, 902908.
69. Nappo, F, Esposito, K, Cioffi, M et al. (2002) Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol 39, 11451150.
70. van Oostrom, AJ, Rabelink, TJ, Verseyden, C et al. (2004) Activation of leukocytes by postprandial lipemia in healthy volunteers. Atherosclerosis 177, 175182.
71. Blanco-Colio, LM, Valderrama, M, varez-Sala, LA et al. (2000) Red wine intake prevents nuclear factor-kappaB activation in peripheral blood mononuclear cells of healthy volunteers during postprandial lipemia. Circulation 102, 10201026.
72. Erridge, C (2011) The capacity of foodstuffs to induce innate immune activation of human monocytes in vitro is dependent on food content of stimulants of Toll-like receptors 2 and 4. Br J Nutr 105, 1523.
73. Cani, PD, Amar, J, Iglesias, MA et al. (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 17611772.
74. Erridge, C, Attina, T, Spickett, CM et al. (2007) A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 86, 12861292.
75. Lee, JY, Ye, J, Gao, Z et al. (2003) Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J Biol Chem 278, 3704137051.
76. Lee, JY, Zhao, L, Youn, HS et al. (2004) Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1. J Biol Chem 279, 1697116979.
77. Lee, JY, Plakidas, A, Lee, WH et al. (2003) Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids. J Lipid Res 44, 479486.
78. Shi, H, Kokoeva, MV, Inouye, K et al. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116, 30153025.
79. Saberi, M, Woods, NB, de, LC, Schenk, S et al. (2009) Hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10, 419429.
80. Tsukumo, DM, Carvalho-Filho, MA, Carvalheira, JB et al. (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 19861998.
81. Poggi, M, Bastelica, D, Gual, P et al. (2007) C3H/HeJ mice carrying a Toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50, 12671276.
82. Schwartz, EA, Zhang, WY, Karnik, SK et al. (2010) Nutrient modification of the innate immune response: a novel mechanism by which saturated fatty acids greatly amplify monocyte inflammation. Arterioscler Thromb Vasc Biol 30, 802808.
83. Erridge, C & Samani, NJ (2009) Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 29, 19441949.
84. Chavez, JA & Summers, SA (2003) Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Arch Biochem Biophys 419, 101109.
85. Arkan, MC, Hevener, AL, Greten, FR et al. (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11, 191198.
86. Hirosumi, J, Tuncman, G, Chang, L et al. (2002) A central role for JNK in obesity and insulin resistance. Nature 420, 333336.
87. Kim, F, Pham, M, Maloney, E et al. (2008) Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance. Arterioscler Thromb Vasc Biol 28, 19821988.
88. Summers, SA (2006) Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45, 4272.
89. Zigman, JM & Elmquist, JK (2003) Minireview: From anorexia to obesity – the Yin and Yang of body weight control. Endocrinology 144, 37493756.
90. Tao, YX (2009) Mutations in melanocortin-4 receptor and human obesity. Prog Mol Biol Transl Sci 88, 173204.
91. Cone, RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8, 571578.
92. Horvath, TL, Bechmann, I, Naftolin, F et al. (1997) Heterogeneity in the neuropeptide Y-containing neurons of the rat arcuate nucleus: GABAergic and non-GABAergic subpopulations. Brain Res 756, 283286.
93. Theodosis, DT, Poulain, DA & Oliet, SH (2008) Activity-dependent structural and functional plasticity of astrocyte-neuron interactions. Physiol Rev 88, 983–1008.
94. Horvath, TL, Sarman, B, Garcia-Caceres, C et al. (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci USA 107, 1487514880.
95. Badoer, E (2010) Microglia: activation in acute and chronic inflammatory states and in response to cardiovascular dysfunction. Int J Biochem Cell Biol 42, 15801585.
96. Gloaguen, I, Costa, P, Demartis, A et al. (1997) Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance. Proc Natl Acad Sci USA 94, 64566461.
97. Kokoeva, MV, Yin, H & Flier, JS (2005) Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310, 679683.
98. Ettinger, MP, Littlejohn, TW, Schwartz, SL et al. (2003) Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA 289, 18261832.
99. Lambert, PD, Anderson, KD, Sleeman, MW et al. (2001) Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Proc Natl Acad Sci USA 98, 46524657.
100. Sleeman, MW, Garcia, K, Liu, R et al. (2003) Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice. Proc Natl Acad Sci USA 100, 1429714302.
101. Sleeman, MW, Anderson, KD, Lambert, PD et al. (2000) The ciliary neurotrophic factor and its receptor, CNTFR alpha. Pharm Acta Helv 74, 265272.
102. Pencea, V, Bingaman, KD, Wiegand, SJ et al. (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21, 67066717.
103. Xu, Y, Tamamaki, N, Noda, T et al. (2005) Neurogenesis in the ependymal layer of the adult rat 3rd ventricle. Exp Neurol 192, 251264.
104. Kokoeva, MV, Yin, H & Flier, JS (2007) Evidence for constitutive neural cell proliferation in the adult murine hypothalamus. J Comp Neurol 505, 209220.
105. Muppidi, JR, Tschopp, J & Siegel, RM (2004) Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity 21, 461465.
106. Mkaddem, SB, Bens, M & Vandewalle, A (2010) Differential activation of Toll-like receptor-mediated apoptosis induced by hypoxia. Oncotarget 1, 741750.
107. Moraes, JC, Coope, A, Morari, J et al. (2009) High-fat diet induces apoptosis of hypothalamic neurons. PLoS One 4, e5045.
108. Lee, DA, Bedont, JL, Pak, T et al. (2012) Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat Neurosci 15, 700702.
109. Frayn, KN & Coppack, SW (1992) Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82, 18.
110. Frayn, KN, Williams, CM & Arner, P (1996) Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases? Clin Sci 90, 243253.
111. Karpe, F, Dickmann, JR & Frayn, KN (2011) Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 60, 24412449.
112. Erion, DM & Shulman, GI (2010) Diacylglycerol-mediated insulin resistance. Nat Med 16, 400402.
113. Unger, RH, Clark, GO, Scherer, PE et al. (2010) Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 1801, 209214.
114. Karmi, A, Iozzo, P, Viljanen, A et al. (2010) Increased brain fatty acid uptake in metabolic syndrome. Diabetes 59, 21712177.
115. Chang, GQ, Karatayev, O, Davydova, Z et al. (2004) Circulating triglycerides impact on orexigenic peptides and neuronal activity in hypothalamus. Endocrinology 145, 39043912.
116. Obici, S, Feng, Z, Morgan, K et al. (2002) Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271275.
117. Loftus, TM, Jaworsky, DE, Frehywot, GL et al. (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 23792381.
118. Kim, EK, Miller, I, Landree, LE et al. (2002) Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. Am J Physiol 283, E867E879.
119. Lopez, M, Lelliott, CJ, Tovar, S et al. (2006) Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 55, 13271336.
120. Kaushik, S, Rodriguez-Navarro, JA, Arias, E et al. (2011) Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab 14, 173183.
121. Lopez, M, Varela, L, Vazquez, MJ et al. (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 6, 10011008.
122. Lopez, M, Lage, R, Saha, AK et al. (2008) Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 7, 389399.
123. Mizuno, TM & Mobbs, CV (1999) Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814817.
124. Liu, T, Kong, D, Shah, BP et al. (2012) Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73, 511522.
125. Cowley, MA, Smith, RG, Diano, S et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649661.
126. Kamegai, J, Tamura, H, Shimizu, T et al. (2000) Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 141, 47974800.
127. Quan, W, Kim, HK, Moon, EY et al. (2012) Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153, 18171826.
128. Meng, Q & Cai, D (2011) Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkappaB kinase beta (IKKbeta)/NF-kappaB pathway. J Biol Chem 286, 3232432332.
129. Yi, CX, Habegger, KM, Chowen, JA et al. (2011) A role for astrocytes in the central control of metabolism. Neuroendocrinology 93, 143149.
130. Holland, WL, Bikman, BT, Wang, LP et al. (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121, 18581870.
131. Martinez de Morentin, PB, Varela, L, Ferno, J et al. (2010) Hypothalamic lipotoxicity and the metabolic syndrome. Biochim Biophys Acta 1801, 350361.
132. Cintra, DE, Ropelle, ER, Moraes, JC et al. (2012) Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity. PLoS One 7, e30571.
133. Yorimitsu, T & Klionsky, DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12, 15421552.
134. Butler, D & Bahr, BA (2006) Oxidative stress and lysosomes: CNS-related consequences and implications for lysosomal enhancement strategies and induction of autophagy. Antioxid Redox Signal 8, 185196.
135. Yorimitsu, T, Nair, U, Yang, Z et al. (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281, 3029930304.
136. Fujishima, Y, Nishiumi, S, Masuda, A et al. (2011) Autophagy in the intestinal epithelium reduces endotoxin-induced inflammatory responses by inhibiting NF-kappaB activation. Arch Biochem Biophys 506, 223235.
137. Raichle, ME & Gusnard, DA (2002) Appraising the brain's energy budget. Proc Natl Acad Sci USA 99, 1023710239.
138. Melov, S (2004) Modeling mitochondrial function in aging neurons. Trends Neurosci 27, 601606.
139. Lin, MT & Beal, MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787795.
140. Matsuzawa-Nagata, N, Takamura, T, Ando, H et al. (2008) Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 57, 10711077.
141. Benani, A, Troy, S, Carmona, MC et al. (2007) Role for mitochondrial reactive oxygen species in brain lipid sensing: redox regulation of food intake. Diabetes 56, 152160.
142. Leloup, C, Magnan, C, Benani, A et al. (2006) Mitochondrial reactive oxygen species are required for hypothalamic glucose sensing. Diabetes 55, 20842090.
143. Colombani, AL, Carneiro, L, Benani, A et al. (2009) Enhanced hypothalamic glucose sensing in obesity: alteration of redox signaling. Diabetes 58, 21892197.
144. Schrader, M & Fahimi, HD (2006) Peroxisomes and oxidative stress. Biochim Biophys Acta 1763, 17551766.
145. Du, X, Edelstein, D, Obici, S et al. (2006) Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest 116, 10711080.
146. Yamagishi, SI, Edelstein, D, Du, XL et al. (2001) Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 276, 2509625100.
147. Walter, P & Ron, D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 10811086.
148. Fonseca, SG, Gromada, J & Urano, F (2011) Endoplasmic reticulum stress and pancreatic beta-cell death. Trends Endocrinol Metab 22, 266274.
149. Ozcan, U, Cao, Q, Yilmaz, E et al. (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457461.
150. Ozcan, U, Yilmaz, E, Ozcan, L et al. (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 11371140.
151. Ron, D & Walter, P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8, 519529.
152. Hosoi, T, Sasaki, M, Miyahara, T et al. (2008) Endoplasmic reticulum stress induces leptin resistance. Mol Pharmacol 74, 16101619.
153. Woods, SC, D'Alessio, DA, Tso, P et al. (2004) Consumption of a high-fat diet alters the homeostatic regulation of energy balance. Physiol Behav 83, 573578.
154. Wang, J, Obici, S, Morgan, K et al. (2001) Overfeeding rapidly induces leptin and insulin resistance. Diabetes 50, 27862791.
155. Xu, AW, Kaelin, CB, Takeda, K et al. (2005) PI3K integrates the action of insulin and leptin on hypothalamic neurons. J Clin Invest 115, 951958.
156. Morton, GJ, Gelling, RW, Niswender, KD et al. (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2, 411420.
157. Kim, MS, Pak, YK, Jang, PG et al. (2006) Role of hypothalamic FoxO1 in the regulation of food intake and energy homeostasis. Nat Neurosci 9, 901906.
158. Kitamura, T, Feng, Y, Kitamura, YI et al. (2006) Forkhead protein FoxO1 mediates AgRP-dependent effects of leptin on food intake. Nat Med 12, 534540.
159. Howard, JK & Flier, JS (2006) Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab 17, 365371.
160. Kievit, P, Howard, JK, Badman, MK et al. (2006) Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab 4, 123132.
161. Bence, KK, Delibegovic, M, Xue, B et al. (2006) Neuronal PTP1B regulates body weight, adiposity and leptin action. Nat Med 12, 917924.
162. Prada, PO, Zecchin, HG, Gasparetti, AL et al. (2005) Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion. Endocrinology 146, 15761587.
163. Romanatto, T, Cesquini, M, Amaral, ME et al. (2007) TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient – effects on leptin and insulin signaling pathways. Peptides 28, 10501058.
164. Zabolotny, JM, ce-Hanulec, KK, Stricker-Krongrad, A et al. (2002) PTP1B regulates leptin signal transduction in vivo . Dev Cell 2, 489495.
165. Zabolotny, JM, Kim, YB, Welsh, LA et al. (2008) Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem 283, 1423014241.
166. Ito, Y, Banno, R, Hagimoto, S et al. (2012) TNFalpha increases hypothalamic PTP1B activity via the NFkappaB pathway in rat hypothalamic organotypic cultures. Regul Pept 174, 5864.
167. Ozcan, L, Ergin, AS, Lu, A et al. (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9, 3551.
168. Kleinridders, A, Schenten, D, Konner, AC et al. (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10, 249259.
169. Lehnardt, S, Massillon, L, Follett, P et al. (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 100, 85148519.
170. Choi, SJ, Kim, F, Schwartz, MW et al. (2010) Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids. Am J Physiol 298, E1122E1130.
171. Mayer, CM & Belsham, DD (2010) Palmitate attenuates insulin signaling and induces endoplasmic reticulum stress and apoptosis in hypothalamic neurons: rescue of resistance and apoptosis through adenosine 5′ monophosphate-activated protein kinase activation. Endocrinology 151, 576585.