Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-7479d7b7d-k7p5g Total loading time: 0 Render date: 2024-07-08T14:14:04.987Z Has data issue: false hasContentIssue false

4 - Leptin and insulin as adiposity signals

Published online by Cambridge University Press:  15 September 2009

By
Kevin D. Niswender
Edited by
Jenni Harvey  and
Dominic J. Withers
Kevin D. Niswender
Affiliation:
Diabetes, Endocrinology and Metabolism, 715, Preston Research Building, Vanderbilt University, Medical Center, 2220, Pierce Avenue Nashville, TN 37232–6303, USA
Jenni Harvey
Affiliation:
University of Dundee
Dominic J. Withers
Affiliation:
Imperial College of Science, Technology and Medicine, London
Get access

Summary

Summary

Obesity is an epidemic in the USA and worldwide. Despite a rapid increase in the burden of obesity, scientific evidence indicates that body adiposity is a tightly regulated physiological variable. Current models implicate a classical endocrine feedback loop in the process termed energy homeostasis. Both the pancreatic β cell-derived hormone insulin and the adipocyte-derived hormone leptin are secreted in proportion to fat mass and, thus, signal the status of body energy stores to the hypothalamus. Key hypothalamic nuclei contain neurons that respond directly to insulin and leptin and integrate these and other signals in order to regulate food intake and energy homeostasis through a series of complex neuronal circuits.

Although the personal, societal and economic costs of obesity are staggering, the medical research community has yet to develop definitive therapies. Recent advances in our understanding of the interactions of insulin and leptin with hypothalamic target neurons has shed light upon potential pathophysiological mechanisms and therefore therapeutic targets. In this chapter, basic mechanisms of energy homeostasis will be presented in the context of an adiposity negative feedback model with the hormones insulin and leptin serving an important role. This model will then be extended and discussed in the context of the pathophysiology of obesity.

Introduction

Obesity is an international health epidemic (Kopelman, 2000; Mokdad et al., 2001) afflicting 1.7 billion people worldwide (James, 2003) and has surpassed infectious disease and under-nutrition as the major threat to health in most parts of the world.

Type
Chapter
Information
Neurobiology of Obesity , pp. 83 - 126
Publisher: Cambridge University Press
Print publication year: 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Air, E. L., Benoit, S. C., Blake Smith, K. A., Clegg, D. J. & Woods, S. C. (2002). Acute third ventricular administration of insulin decreases food intake in two paradigms. Pharmacol. Biochem. Behav. 72, 423–9.CrossRefGoogle ScholarPubMed
Anderson, J. W., Kendall, C. W. & Jenkins, D. J. (2003). Importance of weight management in type 2 diabetes: review with meta-analysis of clinical studies. J. Am. Coll. Nutr. 22, 331–9.CrossRefGoogle ScholarPubMed
Anderwald, C., Muller, G., Koca, G., Furnsinn, C., Waldhausl, W. & Roden, M. (2002). Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2. Mol. Endocrinol. 16, 1612–28.CrossRefGoogle ScholarPubMed
Association, A. D. (2000). National Diabetes Fact Sheet. http://www.diabetes.org/info/facts/facts_natl.jsp.
Astrup, A. & Finer, N. (2000). Redefining type 2 diabetes: ‘diabesity’ or ‘obesity dependent diabetes mellitus’? Obes. Rev. 1, 57–9.CrossRefGoogle ScholarPubMed
Bagdade, J. D., Bierman, E. L. & Porte, D. Jr. (1967). The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J. Clin. Invest. 46, 1549–57.CrossRefGoogle ScholarPubMed
Banks, A. S., Davies, S. M., Bates, S. H. & Myers, M. G. Jr. (2000). Activation of downstream signals by the long form of the leptin receptor. J. Biol. Chem. 275, 14 563–72.CrossRefGoogle Scholar
Banks, W. A. & Farrell, C. L. (2003). Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible. Am. J. Physiol. Endocrinol. Metab. 285, E10–15.CrossRefGoogle ScholarPubMed
Banks, W. A., Kastin, A. J., Huang, W., Jaspan, J. B. & Maness, L. M. (1996). Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305–11.CrossRefGoogle ScholarPubMed
Bates, S. H. & Myers, M. G. (2003). The role of leptin–>STAT3 signaling in neuroendocrine function: an integrative perspective. J. Mol. Med. Epub 2003. Published 2004, J. Mol. Med. 82, 12–20.CrossRefGoogle Scholar
Bates, S. H., Stearns, W. H., Dundon, T. A.et al. (2003). STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421, 856–9.CrossRefGoogle Scholar
Baura, G. D., Foster, D. M., Porte, D. Jr.et al. (1993). Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J. Clin. Invest. 92, 1824–30.CrossRefGoogle Scholar
Beck, B., Burlet, A., Nicolas, J. P. & Burlet, C. (1990). Hypothalamic neuropeptide Y (NPY) in obese Zucker rats: implications in feeding and sexual behaviors. Physiol. Behav. 47, 449–53.CrossRefGoogle ScholarPubMed
Benoit, S. C., Air, E. L., Coolen, L. M.et al. (2002). The catabolic action of insulin in the brain is mediated by melanocortins. J. Neurosci. 22, 9048–52.CrossRefGoogle ScholarPubMed
Bernstein, I. L., Lotter, E. C., Kulkosky, P. J., Porte, D. Jr. & Woods, S. C. (1975). Effect of force-feeding upon basal insulin levels of rats. Proc. Soc. Exp. Biol. Med. 150, 546–8.CrossRefGoogle ScholarPubMed
Berridge, K. C. (1991). Modulation of taste affect by hunger, caloric satiety, and sensory specific satiety in the rat. Appetite 16, 103–20.CrossRefGoogle ScholarPubMed
Berridge, K. C. (1996). Food reward: brain substrates of wanting and liking. Neurosci. Biobehav. Rev. 20, 1–25.CrossRefGoogle Scholar
Berridge, K. C. & Grill, H. J. (1983). Alternating ingestive and aversive consummatory responses suggest a two-dimensional analysis of palatability in rats. Behav. Neurosci. 97, 563–73.CrossRefGoogle ScholarPubMed
Berthoud, H. R. (2002). Multiple neural systems controlling food intake and body weight. Neurosci. Biobehav. Rev. 26, 393–428.CrossRefGoogle ScholarPubMed
Berthoud, H. R. (2004). Mind versus metabolism in the control of food intake and energy balance. Physiol. Behav. 81, 781–93.CrossRefGoogle ScholarPubMed
Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. & Flier, J. S. (1998). Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell. 1, 619–25.CrossRefGoogle ScholarPubMed
Bjorbaek, C., El-Haschimi, K., Frantz, J. D. & Flier, J. S. (1999). The role of SOCS-3 in leptin signaling and leptin resistance. J. Biol. Chem. 274, 30 059–65.CrossRefGoogle ScholarPubMed
Bravata, D. M., Sanders, L., Huang, J., Krumholz, H. M., Olkin, I. & Gardner, C. D. (2003). Efficacy and safety of low-carbohydrate diets: a systematic review. J. Am. Med. Assoc. 289, 1837–50.CrossRefGoogle ScholarPubMed
Bray, G. A. (2003). Risks of obesity. Endocrinol. Metab. Clin. North Am. 32, 787–804, viii.CrossRefGoogle ScholarPubMed
Brehm, B. J., Seeley, R. J., Daniels, S. R. & D'Alessio, D. A. (2003). A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J. Clin. Endocrinol. Metab. 88, 1617–23.CrossRefGoogle Scholar
Brobeck, J., Tepperman, J. & Long, C. (1943). Experimental hypothalamic hyperphagia in the albino rat. Yale J. Biol. Med. 15, 831.Google ScholarPubMed
Bruning, J. C., Gautam, D., Burks, D. J.et al. (2000). Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–5.CrossRefGoogle ScholarPubMed
Burks, D. J., Mora, J. F., Schubert, M.et al. (2000). IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407, 377–82.Google ScholarPubMed
Butler, A. A. (2006). The melanocortin system and energy balance. Peptides 27, 281–90.CrossRefGoogle ScholarPubMed
Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R. & Burn, P. (1995). Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–9.CrossRefGoogle ScholarPubMed
Capaldi, E. D., Hunter, M. J. & Lyn, S. A. (1997). Conditioning with taste as the CS in conditioned flavor preference learning. An. Learn. Behav. 25, 427–36.CrossRefGoogle Scholar
Carlson, M. G. & Campbell, P. J. (1993). Intensive insulin therapy and weight gain in IDDM. Diabetes 42, 1700–7.CrossRefGoogle ScholarPubMed
Carvalheira, J. B., Ribeiro, E. B., Araujo, E. P.et al. (2003). Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats. Diabetologia 46, 1629–40.CrossRefGoogle ScholarPubMed
Clegg, D. J., Riedy, C. A., Smith, K. A., Benoit, S. C. & Woods, S. C. (2003). Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52, 682–7.CrossRefGoogle ScholarPubMed
Cohen, P., Zhao, C., Cai, X.et al. (2001). Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–21.CrossRefGoogle ScholarPubMed
Coll, A. P., Farooqi, I. S., Challis, B. G., Yeo, G. S. & O'Rahilly, S. (2004). Proopiomelanocortin and energy balance: insights from human and murine genetics. J. Clin. Endocrinol. Metab. 89, 2557–62.CrossRefGoogle ScholarPubMed
Cone, R. D., Cowley, M. A., Butler, A. A., Fan, W., Marks, D. L. & Low, M. J. (2001). The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int. J. Obes. Relat. Metab. Disord. 25 Suppl. 5, S63–7.CrossRefGoogle ScholarPubMed
Considine, R. V., Sinha, M. K., Heiman, M. L.et al. (1996). Serum immunoreactive-leptin concentrations in normal-weight and obese humans [see comments]. N. Engl. J. Med. 334, 292–5.CrossRefGoogle Scholar
Control, C. F. D. (2003) Overweight and obesity, obesity trends. http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/index.htm.
Corkey, B. E., Deeney, J. T., Yaney, G. C., Tornheim, K. & Prentki, M. (2000). The role of long-chain fatty acyl-CoA esters in beta-cell signal transduction. J. Nutr. 130, 299S–304S.CrossRefGoogle ScholarPubMed
Corp, E. S., Woods, S. C., Porte, D. Jr., Dorsa, D. M., Figlewicz, D. P. & Baskin, D. G. (1986). Localization of 125I-insulin binding sites in the rat hypothalamus by quantitative autoradiography. Neurosci. Lett. 70, 17–22.CrossRefGoogle ScholarPubMed
Cowley, M. A., Smart, J. L., Rubinstein, M.et al. (2001). Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–4.CrossRefGoogle ScholarPubMed
Cusi, K., Maezono, K., Osman, A.et al. (2000). Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle. J. Clin. Invest. 105, 311–20.CrossRefGoogle ScholarPubMed
Dallman, M. F., Pecoraro, N., Akana, S. F.et al. (2003). Chronic stress and obesity: a new view of “comfort food”. Proc. Natl. Acad. Sci. USA 100, 11 696–701.CrossRefGoogle ScholarPubMed
Luca, C., Kowalski, T. J., Zhang, Y.et al. (2005). Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. J. Clin. Invest. 115, 3484–93.CrossRefGoogle ScholarPubMed
Defronzo, R. A. (1988). Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37, 667–87.CrossRefGoogle ScholarPubMed
Despres, J. P., Golay, A. & Sjostrm, L. (2005). Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 353, 2121–34.CrossRefGoogle ScholarPubMed
Dhillon, H., Zigman, J. M., Ye, C.et al. (2006). Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203.CrossRefGoogle ScholarPubMed
Dresner, I., Laurent, D., Marcucci, M.et al. (1999). Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103, 253–9.CrossRefGoogle ScholarPubMed
Dryden, S., Pickavance, L., Henderson, L. & Williams, G. (1998). Hyperphagia induced by hypoglycemia in rats is independent of leptin and hypothalamic neuropeptide Y (NPY). Peptides 19, 1549–55.CrossRefGoogle Scholar
Eckel, R. H., Grundy, S. M. & Zimmet, P. Z. (2005). The metabolic syndrome. Lancet 365, 1415–28.CrossRefGoogle ScholarPubMed
El-Assaad, W., Buteau, J., Peyot, M. L.et al. (2003). Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 144, 4154–63.CrossRefGoogle ScholarPubMed
El-Haschimi, K., Pierroz, D. D., Hileman, S. M., Bjorbaek, C. & Flier, J. S. (2000). Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J. Clin. Invest. 105, 1827–32.CrossRefGoogle ScholarPubMed
Elchebly, M., Payette, P., Michaliszyn, E.et al. (1999). Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–8.CrossRefGoogle ScholarPubMed
Elias, C. F., Aschkenasi, C., Lee, C.et al. (1999). Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–86.CrossRefGoogle ScholarPubMed
Emanuelli, B., Peraldi, P., Filloux, C., Sawka-Verhelle, D., Hilton, D. & Obberghen, E. (2000). SOCS-3 is an insulin-induced negative regulator of insulin signaling. J. Biol Chem. 275, 15 985–91.CrossRefGoogle ScholarPubMed
Emanuelli, B., Peraldi, P., Filloux, C.et al. (2001). SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J. Biol. Chem. 276, 47 944–9.CrossRefGoogle ScholarPubMed
Erickson, J. C., Hollopeter, G. & Palmiter, R. D. (1996). Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274, 1704–7.CrossRefGoogle Scholar
Farooqi, I. S., Jebb, S. A., Langmack, G.et al. (1999). Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–84.CrossRefGoogle Scholar
Faulconbridge, L. F., Cummings, D. E., Kaplan, J. M. & Grill, H. J. (2003). Hyperphagic effects of brainstem ghrelin administration. Diabetes 52, 2260–5.CrossRefGoogle ScholarPubMed
Faulconbridge, L. F., Grill, H. J. & Kaplan, J. M. (2005). Distinct forebrain and caudal brainstem contributions to the neuropeptide Y mediation of ghrelin hyperphagia. Diabetes 54, 1985–93.CrossRefGoogle ScholarPubMed
Figlewicz, D. P. (2003a). Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R882–92.CrossRefGoogle Scholar
Figlewicz, D. P. (2003b). Insulin, food intake, and reward. Semin. Clin. Neuropsych. 8, 82–93.CrossRefGoogle Scholar
Figlewicz, D. P., Higgins, M. S., Ng-Evans, S. B. & Havel, P. J. (2001). Leptin reverses sucrose-conditioned place preference in food-restricted rats. Physiol. Behav. 73, 229–34.CrossRefGoogle ScholarPubMed
Figlewicz, D. P., Evans, S. B., Murphy, J., Hoen, M. & Baskin, D. G. (2003). Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res. 964, 107–15.CrossRefGoogle ScholarPubMed
Figlewicz, D. P., Bennett, J., Evans, S. B., Kaiyala, K., Sipols, A. J. & Benoit, S. C. (2004). Intraventricular insulin and leptin reverse place preference conditioned with high fat diet in rats. Behav. Neurosci. 118, 479–87.CrossRefGoogle ScholarPubMed
Flier, J. S. (1998). Clinical review 94: What's in a name? In search of leptin's physiologic role. J. Clin. Endocrinol. Metab. 83, 1407–13.Google Scholar
Foster, G. D., Wyatt, H. R., Hill, J. O.et al. (2003). A randomized trial of a low carbohydrate diet for obesity. N. Engl. J. Med. 348, 2082–90.CrossRefGoogle ScholarPubMed
Foster, L. A., Ames, N. K. & Emery, R. S. (1991). Food intake and serum insulin responses to intraventricular infusions of insulin and IGF-I. Physiol. Behav. 50, 745–9.CrossRefGoogle ScholarPubMed
Garofalo, R. S. (2002). Genetic analysis of insulin signaling in Drosophila. Trends Endocrinol. Metab. 13, 156–62.CrossRefGoogle ScholarPubMed
Georgescu, D., Sears, R. M., Hommel, J. D.et al. (2005). The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. J. Neurosci. 25, 2933–40.CrossRefGoogle ScholarPubMed
Griffin, M. E., Marcucci, M. J., Cline, G. W.et al. (1999). Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48, 1270–4.CrossRefGoogle ScholarPubMed
Grill, H. J. & Kaplan, J. M. (2002). The neuroanatomical axis for control of energy balance. Front. Neuroendocrinol. 23, 2–40.CrossRefGoogle ScholarPubMed
Grill, H. J., Schwartz, M. W., Kaplan, J. M., Foxhall, J. S., Breininger, J. & Baskin, D. G. (2002). Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143, 239–46.CrossRefGoogle ScholarPubMed
Gulick, A. (1922). A study of weight regulation in the adult human body during over nutrition. Am. J. Physiol. 60, 371–95.Google Scholar
Halaas, J. L., Gajiwala, K. S., Maffei, M.et al. (1995). Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–6.CrossRefGoogle ScholarPubMed
Harris, R. B., Kasser, T. R. & Martin, R. J. (1986). Dynamics of recovery of body composition after overfeeding, food restriction or starvation of mature female rats. J. Nutr. 116, 2536–46.CrossRefGoogle ScholarPubMed
Harvey, J., McKay, N. G., Walker, K. S., Kaay, J., Downes, C. P. & Ashford, M. L. (2000). Essential role of phosphoinositide 3-kinase in leptin-induced K(ATP) channel activation in the rat CRI-G1 insulinoma cell line. J. Biol. Chem. 275, 4660–9.CrossRefGoogle ScholarPubMed
Hawkins, M., Tonelli, J., Kishore, P.et al. (2003). Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes. Diabetes 52, 2748–58.CrossRefGoogle ScholarPubMed
He, W., Lam, T. K., Obici, S. & Rossetti, L. (2006). Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat. Neurosci. 9, 227–33.CrossRefGoogle ScholarPubMed
Hill, J. O., Dorton, J., Sykes, M. N. & Digirolamo, M. (1989). Reversal of dietary obesity is influenced by its duration and severity. Int. J. Obes. 13, 711–22.Google ScholarPubMed
Houmard, J. A., Tanner, C. J., Yu, C.et al. (2002). Effect of weight loss on insulin sensitivity and intramuscular long-chain fatty acyl-CoAs in morbidly obese subjects. Diabetes 51, 2959–63.CrossRefGoogle ScholarPubMed
Howard, J. K., Cave, B. J., Oksanen, L. J., Tzameli, I., Bjorbaek, C. & Flier, J. S. (2004). Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat. Med. 10, 734–8.CrossRefGoogle ScholarPubMed
James, P. (2003). Call for obesity review as overweight numbers reach 1.7 billion. International Obesity Task Force press release.Google Scholar
Kaiyala, K. J., Prigeon, R. L., Kahn, S. E., Woods, S. C. & Schwartz, M. W. (2000). Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49, 1525–33.CrossRefGoogle ScholarPubMed
Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J. & Waterfield, W. D. (2001). Cellular function of phosphoinositide 3-kinase: implications for development, homeostasis, and cancer. Annu. Rev. Cell. Dev. Biol. 17, 615–75.CrossRefGoogle ScholarPubMed
Rhinehart, Keen E., Kalra, S. P. & Kalra, P. S. (2004). Neuropeptidergic characterization of the leptin receptor mutated obese Koletsky rat. Regul. Pept. 119, 3–10.CrossRefGoogle Scholar
Kellerer, M., Koch, M., Metzinger, E., Mushack, J., Capp, E. & Haring, H. U. (1997). Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK- 2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 40, 1358–62.CrossRefGoogle ScholarPubMed
Kennedy, G. C. (1953). The role of depot fat in the hypothalamic control of food intake in the rat. Proc. R. Soc. Lond. 140, 579–592.CrossRefGoogle ScholarPubMed
Kido, Y., Nakae, J. & Accili, D. (2001). Clinical review 125: the insulin receptor and its cellular targets. J. Clin. Endocrinol. Metab. 86, 972–9.Google ScholarPubMed
Kim, E. M., O'Hare, E., Grace, M. K., Welch, C. C., Billington, C. J. & Levine, A. S. (2000). ARC POMC mRNA and PVN alpha-MSH are lower in obese relative to lean zucker rats. Brain Res. 862, 11–6.CrossRefGoogle ScholarPubMed
Kim, J. K., Kim, Y. J., Fillmore, J. J.et al. (2001). Prevention of fat-induced insulin resistance by salicylate. J. Clin. Invest. 108, 437–46.CrossRefGoogle ScholarPubMed
Knowler, W. C., Barrett-Connor, E., Fowler, S. E.et al. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403.Google ScholarPubMed
Kopelman, P. G. (2000). Obesity as a medical problem. Nature 404, 635–43.CrossRefGoogle ScholarPubMed
Krisch, B. & Leonhardt, H. (1978). The functional and structural border of the neurohemal region of the median eminence. Cell Tissue Res. 192, 327–39.CrossRefGoogle ScholarPubMed
Kurrimbux, D., Gaffen, Z., Farrell, C. L., Martin, D. & Thomas, S. A. (2004). The involvement of the blood–brain and the blood–cerebrospinal fluid barriers in the distribution of leptin into and out of the rat brain. Neurosci. 123, 527–36.CrossRefGoogle ScholarPubMed
Lam, T. K., Schwartz, G. J. & Rossetti, L. (2005). Hypothalamic sensing of fatty acids. Nat. Neurosci. 8, 579–84.CrossRefGoogle ScholarPubMed
Lee, G. H., Pronca, R., Montez, J. M.et al. (1996). Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–5.CrossRefGoogle ScholarPubMed
Lee, S. S., Kennedy, S., Tolonen, A. C. & Ruvkun, G. (2003). DAF-16 target genes that control C. elegans life-span and metabolism. Science 300, 644–7.CrossRefGoogle ScholarPubMed
Leibel, R. L. (2002). The role of leptin in the control of body weight. Nutr. Rev. 60, S15–19; discussion S68–84, 85–7.CrossRefGoogle ScholarPubMed
Levine, A. S., Kotz, C. M. & Gosnell, B. A. (2003a). Sugars and fats: the eurobiology of preference. J. Nutr. 133, 831S–4S.CrossRefGoogle Scholar
Levine, A. S., Kotz, C. M. & Gosnell, B. A. (2003b). Sugars: hedonic aspects, neuroregulation, and energy balance. Am. J. Clin. Nutr. 78, 834S–42S.CrossRefGoogle Scholar
Lillioja, S. & Bogardus, C. (1988a). Insulin resistance in Pima Indians. A combined effect of genetic predisposition and obesity-related skeletal muscle cell hypertrophy. Acta. Med. Scand. Suppl. 723, 103–19.Google Scholar
Lillioja, S. & Bogardus, C. (1988b). Obesity and insulin resistance: lessons learned from the Pima Indians. Diabetes Metab. Rev. 4, 517–40.CrossRefGoogle Scholar
Lopez, M., Tovar, S., Vazquez, M. J., Nogueiras, R., Senaris, R. & Dieguez, C. (2005). Sensing the fat: fatty acid metabolism in the hypothalamus and the melanocortin system. Peptides 26, 1753–8.CrossRefGoogle ScholarPubMed
MacDonald, A. F., Billington, C. J. & Levine, A. S. (2003). Effects of the opioid antagonist naltrexone on feeding induced by DAMGO in the ventral tegmental area and in the nucleus accumbens shell region in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R999–1004.CrossRefGoogle ScholarPubMed
Marks, J. L., Porte, D. Jr., Stahl, W. L. & Baskin, D. G. (1990). Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127, 3234–6.CrossRefGoogle ScholarPubMed
Marshall, N. B., Barrnett, R. J. & Mayer, J. (1955). Hypothalamic lesions in goldthioglucose injected mice. Proc. Soc. Exp. Biol. Med. 90, 240–4.CrossRefGoogle ScholarPubMed
Mayer, J., French, R. G., Zighera, C. F. & Barrnett, R. J. (1955). Hypothalamic obesity in the mouse: production, description and metabolic characteristics. Am. J. Physiol. 182, 75–82.Google ScholarPubMed
McGarry, J. D. (2001). Travels with carnitine palmitoyltransferase I: from liver to germ cell with stops in between. Biochem. Soc. Trans. 29, 241–5.CrossRefGoogle ScholarPubMed
Merchenthaler, I. (1991). Neurons with access to the general circulation in the central nervous system of the rat: a retrograde tracing study with fluoro-gold. Neuroscience 44, 655–62.CrossRefGoogle ScholarPubMed
Mirshamsi, S., Laidlaw, H. A., Ning, K.et al. (2004). Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and KATP channel activation. BMC Neurosci. 5, 54.CrossRefGoogle ScholarPubMed
Mizuno, T. M., Kleopoulos, S. P., Bergen, H. T., Roberts, J. L., Priest, C. A. & Mobbs, C. V. (1998). Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47, 294–7.CrossRefGoogle Scholar
Mokdad, A. H., Ford, E. S., Bowman, B. A.et al. (2000). Diabetes trends in the U.S.: 1990–1998. Diabetes Care 23, 1278–83.CrossRefGoogle ScholarPubMed
Mokdad, A. H., Bowman, B. A., Ford, E. S., Vinicor, F., Marks, J. S. & Koplan, J. P. (2001). The continuing epidemics of obesity and diabetes in the United States. J. Am. Med. Assoc. 286, 1195–200.CrossRefGoogle ScholarPubMed
Montague, C. T., Farooqi, I. S., Whitehead, J. P.et al. (1997). Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–8.CrossRefGoogle ScholarPubMed
Mori, H., Hanada, R., Hanada, T.et al. (2004). Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10, 739–43.CrossRefGoogle ScholarPubMed
Munzberg, H. & Myers, M. G. Jr. (2005). Molecular and anatomical determinants of central leptin resistance. Nat. Neurosci. 8, 566–70.CrossRefGoogle ScholarPubMed
Munzberg, H., Flier, J. S. & Bjorbaek, C. (2004). Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology 145, 4880–9.CrossRefGoogle ScholarPubMed
Myers, M. G. Jr. (2004). Leptin receptor signaling and the regulation of mammalian physiology. Rec. Prog. Horm. Res. 59, 287–304.CrossRefGoogle ScholarPubMed
Neel, J. V. (1999). The “thrifty genotype” in 1998. Nutr. Rev. 57, S2–9.CrossRefGoogle Scholar
Neel, J. V., Weder, A. B. & Julius, S. (1998). Type II diabetes, essential hypertension, and obesity as “syndromes of impaired genetic homeostasis”: the “thrifty genotype” hypothesis enters the 21st century. Perspect Biol. Med. 42, 44–74.CrossRefGoogle ScholarPubMed
Neumann, R. O. (1902). Experimental contributions to the science of human daily nutritional needs with particular regard to the necessary amount of protein (author's experiments). Arch. Hyg. 45, 69–78.Google Scholar
Niswender, K. D. & Schwartz, M. W. (2003). Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front. Neuroendocrinol. 24, 1–10.CrossRefGoogle ScholarPubMed
Niswender, K. D., Morton, G. J., Stearns, W. H., Rhodes, C. J., Myers, M. G. Jr. & Schwartz, M. W. (2001). Key enzyme in leptin-induced anorexia. Nature 413, 795–6.CrossRefGoogle ScholarPubMed
Niswender, K. D., Gallis, B., Blevins, J. E., Corson, M. A., Schwartz, M. W. & Baskin, D. G. (2003a). Immunocytochemical detection of phosphatidylinositol 3-kinase activation by insulin and leptin. J. Histochem. Cytochem. 51, 275–83.CrossRefGoogle Scholar
Niswender, K. D., Morrison, C. D., Clegg, D. J.et al. (2003b). Insulin activation of phosphatidylinositol 3 kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52, 227–31.CrossRefGoogle Scholar
Niswender, K. D., Baskin, D. G. & Schwartz, M. W. (2004a). Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol. Metab. 15, 362–9.CrossRefGoogle Scholar
Niswender, K. D., Clegg, D. J., Morrison, C. D., Morton, G. J. & Benoit, S. C. (2004b). The human obesity epidemic – a physiological perspective. Curr. Med. Chem. – Immun.Endoc. Metab. Agents 4, 91–104.Google Scholar
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G. & Rossetti, L. (2002a). Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci. 5, 566–72.CrossRefGoogle Scholar
Obici, S., Feng, Z., Morgan, K., Stein, D., Karkanias, G. & Rossetti, L. (2002b). Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271–5.CrossRefGoogle Scholar
Obici, S., Wang, J., Chowdury, R.et al. (2002c). Identification of a biochemical link between energy intake and energy expenditure. J. Clin. Invest. 109, 1599–605.CrossRefGoogle Scholar
Ogden, C. L., Flegal, K. M., Carroll, M. D. & Johnson, C. L. (2002). Prevalence and trends in overweight among US children and adolescents, 1999–2000. J. Am. Med. Assoc. 288, 1728–32.CrossRefGoogle Scholar
Ollmann, M. M., Wilson, B. D., Yang, Y. K.et al. (1997). Antagonism of central melanocortin receptors in vitro and in vivo by agouti- related protein. Science 278, 135–8.CrossRefGoogle ScholarPubMed
Ornish, D. (1998). Avoiding revascularization with lifestyle changes: The Multicenter Lifestyle Demonstration Project. Am. J. Cardiol. 82, 72T–76T.CrossRefGoogle ScholarPubMed
Ornish, D., Scherwitz, L. W., Billings, J. H.et al. (1998). Intensive lifestyle changes for reversal of coronary heart disease. J. Am. Med. Assoc. 280, 2001–7.CrossRefGoogle ScholarPubMed
Pasquet, P. & Apfelbaum, M. (1994). Recovery of initial body weight and composition after long-term massive overfeeding in men. Am. J. Clin. Nutr. 60, 861–3.CrossRefGoogle ScholarPubMed
Pasquet, P., Brigant, L., Froment, A.et al. (1992). Massive overfeeding and energy balance in men: the Guru Walla model. Am. J. Clin. Nutr. 56, 483–90.CrossRefGoogle ScholarPubMed
Peraldi, P., Filloux, C., Emanuelli, B., Hilton, D. J. & Van Obberghen, E. (2001). Insulin induces suppressor of cytokine signaling-3 tyrosine phosphorylation through janus-activated kinase. J. Biol. Chem. 276, 24 614–20.CrossRefGoogle ScholarPubMed
Pi-Sunyer, F. X., Aronne, L. J., Heshmati, H. M., Devin, J. & Rosenstock, J. (2006). Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. J. Am. Med. Assoc. 295, 761–75.CrossRefGoogle ScholarPubMed
Pirozzo, S., Summerbell, C., Cameron, C. & Glasziou, P. (2003). Should we recommend low-fat diets for obesity? Obes. Rev. 4, 83–90.CrossRefGoogle ScholarPubMed
Pocai, A., Muse, E. D. & Rossetti, L. (2006). Did a muscle fuel gauge conquer the brain? Nat. Med. 12, 50–1.CrossRefGoogle Scholar
Poitout, V., Tanaka, Y., Reach, G. & Robertson, R. P. (2001). Oxidative stress, insulin secretion, and insulin resistance. J. Annu. Diabetol. Hotel. Dieu.75–86.Google ScholarPubMed
Pratley, R. E. (1998). Gene-environment interactions in the pathogenesis of type 2 diabetes mellitus: lessons learned from the Pima Indians. Proc. Nutr. Soc. 57, 175–81.CrossRefGoogle ScholarPubMed
Prentki, M., Joly, E., El-Assaad, W. & Roduit, R. (2002). Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 51 Suppl. 3, S405–13.CrossRefGoogle ScholarPubMed
Trillou, Ravinet C., Arnone, M., Delgorge, C.et al. (2003). Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet induced obese mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R345–53.CrossRefGoogle Scholar
Ricci, M. R. & Levin, B. E. (2003). Ontogeny of diet-induced obesity in selectively bred Sprague–Dawley rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 285, R610–18.CrossRefGoogle ScholarPubMed
Roberts, S. B., Young, V. R., Fuss, P.et al. (1990). Energy expenditure and subsequent nutrient intakes in overfed young men. Am. J. Physiol. 259, R461–9.Google ScholarPubMed
Robertson, R. P., Harmon, J., Tran, P. O., Tanaka, Y. & Takahashi, H. (2003). Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52, 581–7.CrossRefGoogle ScholarPubMed
Rogers, P. J. (1985). Returning ‘cafeteria-fed’ rats to a chow diet: negative contrast and effects of obesity on feeding behaviour. Physiol. Behav. 35, 493–9.CrossRefGoogle ScholarPubMed
Rolls, B. J., Rowe, E. A. & Turner, R. C. (1980). Persistent obesity in rats following a period of consumption of a mixed, high energy diet. J. Physiol. 298, 415–27.CrossRefGoogle ScholarPubMed
Rosenbaum, M., Leibel, R. L. & Hirsch, J. (1997). Obesity. N. Engl. J. Med. 337, 396–407.CrossRefGoogle ScholarPubMed
Rothwell, N. J. & Stock, M. J. (1979). Regulation of energy balance in two models of reversible obesity in the rat. J. Comp. Physiol. Psychol. 93, 1024–34.CrossRefGoogle ScholarPubMed
Ruderman, N. B., Saha, A. K., Vavvas, D. & Witters, L. A. (1999). Malonyl-CoA, fuel sensing, and insulin resistance. Am. J. Physiol. 276, E1–E18.Google ScholarPubMed
Rui, L., Yuan, M., Frantz, D., Shoelson, S. & White, M. F. (2002). SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277, 42 394–8.CrossRefGoogle ScholarPubMed
Saad, M. J., Folli, F., Kahn, J. A. & Kahn, C. R. (1993). Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J. Clin. Invest. 92, 2065–72.CrossRefGoogle ScholarPubMed
Saltiel, A. R. & Pessin, J. E. (2002). Insulin signaling pathways in time and space. Trends Cell Biol. 12, 65–71.CrossRefGoogle ScholarPubMed
Samaha, F. F., Iqbal, N., Seshadri, P.et al. (2003). A low-carbohydrate as compared with a low-fat diet in severe obesity. N. Engl. J. Med. 348, 2074–81.CrossRefGoogle ScholarPubMed
Schuit, F. C., Huypens, P., Heimberg, H. & Pipeleers, D. G. (2001). Glucose sensing in pancreatic beta-cells: a model for the study of other glucose-regulated cells in gut, pancreas, and hypothalamus. Diabetes 50, 1–11.CrossRefGoogle Scholar
Schwartz, M. W. & Niswender, K. D. (2004). Adiposity signaling and biological defense against weight gain: absence of protection or central hormone resistance? J. Clin. Endocrinol. Metab. 89, 5889–97.CrossRefGoogle ScholarPubMed
Schwartz, M. W. & Porte, D. Jr. (2005). Diabetes, obesity, and the brain. Science 307, 375–9.CrossRefGoogle Scholar
Schwartz, M. W., Marks, J. L., Sipols, A. J.et al. (1991). Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats. Endocrinology 128, 2645–7.CrossRefGoogle Scholar
Schwartz, M. W., Baskin, D. G., Bukowski, T. R.et al. (1996a). Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45, 531–5.CrossRefGoogle Scholar
Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. & Baskin, D. G. (1996b). Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–6.CrossRefGoogle Scholar
Schwartz, M. W., Woods, S. C., Porte, D. Jr., Seeley, R. J. & Baskin, D. G. (2000). Central nervous system control of food intake. Nature 404, 661–71.CrossRefGoogle ScholarPubMed
Schwartz, M. W., Woods, S. C., Seeley, R. J., Barsh, G. S., Baskin, D. G. & Leibel, R. L. (2003). Is the energy homeostasis system inherently biased toward weight gain? Diabetes 52, 232–8.CrossRefGoogle ScholarPubMed
Semenkovich, C. F. (1997). Regulation of fatty acid synthase (FAS). Prog. Lipid Res. 36, 43–53.CrossRefGoogle Scholar
Shaver, S. W., Pang, J. J., Wainman, D. S., Wall, K. M. & Gross, P. M. (1992). Morphology and function of capillary networks in subregions of the rat tuber cinereum. Cell Tissue Res. 267, 437–48.CrossRefGoogle ScholarPubMed
Shulman, G. I. (2000). Cellular mechanisms of insulin resistance. J. Clin. Invest. 106, 171–6.CrossRefGoogle ScholarPubMed
Sims, E. A., Goldman, R. F., Gluck, C. M., Horton, E. S., Kelleher, P. C. & Rowe, D. W. (1968). Experimental obesity in man. Trans. Assoc. Am. Physicians, 81, 153–70.Google ScholarPubMed
Sims, E. A., Danforth, E. Jr., Horton, E. S., Glennon, J. A., Bray, G. A. & Salans, L. B. (1972). Experimental obesity in man. A progress report. Isr. J. Med. Sci. 8, 813–14.Google Scholar
Sims, E. A., Danforth, E. Jr., Horton, E. S., Bray, G. A., Glennon, J. A. & Salans, L. B. (1973). Endocrine and metabolic effects of experimental obesity in man. Recent Prog. Horm. Res. 29, 457–96.Google ScholarPubMed
Sindelar, D. K., Havel, P. J., Seeley, R. J., Wilkinson, C. W., Woods, S. C. & Schwartz, M. W. (1999). Low plasma leptin levels contribute to diabetic hyperphagia in rats. Diabetes 48, 1275–80.CrossRefGoogle ScholarPubMed
Sipols, A. J., Baskin, D. G. & Schwartz, M. W. (1995). Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 44, 147–51.CrossRefGoogle ScholarPubMed
Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D. & Ashford, M. L. (1997). Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–5.CrossRefGoogle ScholarPubMed
Spanswick, D., Smith, M. A., Mirshamsi, S., Routh, V. H. & Ashford, M. L. (2000). Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat. Neurosci. 3, 757–8.CrossRefGoogle Scholar
Speakman, J. R., Stubbs, R. J. & Mercer, J. G. (2002). Does body mass play a role in the regulation of food intake? Proc. Nutr. Soc. 61, 473–87.CrossRefGoogle ScholarPubMed
Spiegelman, B. M. & Flier, J. S. (2001). Obesity and the regulation of energy balance. Cell 104, 531–43.CrossRefGoogle ScholarPubMed
Stephens, T. W., Basinski, M., Bristow, P. K.et al. (1995). The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530–2.CrossRefGoogle ScholarPubMed
Sugden, M. C., Bulmer, K. & Holness, M. J. (2001). Fuel-sensing mechanisms integrating lipid and carbohydrate utilization. Biochem. Soc. Trans. 29, 272–8.CrossRefGoogle ScholarPubMed
Surwit, R. S., Kuhn, C. M., Cochrane, C., McCubbin, J. A. & Feinglos, M. N. (1988). Diet induced type II diabetes in C57BL/6J mice. Diabetes 37, 1163–7.CrossRefGoogle ScholarPubMed
Tremblay, A., Despres, J. P., Theriault, G., Fournier, G. & Bouchard, C. (1992). Overfeeding and energy expenditure in humans. Am. J. Clin. Nutr. 56, 857–62.CrossRefGoogle ScholarPubMed
Tseng, M. & DeVillis, R. (2000). Correlates of the “western” and “prudent” diet patterns in the us. Ann. Epidemiol. 10, 481–2.CrossRefGoogle ScholarPubMed
Ueki, K., Kondo, T. & Kahn, C. R. (2004a). Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol. Cell Biol. 24, 5434–46.CrossRefGoogle Scholar
Ueki, K., Kondo, T., Tseng, Y. H. & Kahn, C. R. (2004b). Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc. Natl. Acad. Sci. USA, 101, 10 422–7.CrossRefGoogle Scholar
Unger, R. H. (1995). Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44, 863–70.CrossRefGoogle ScholarPubMed
Uusitupa, M., Lindi, V., Loueranta, A., Salopuro, T., Lindstrom, J. & Tuomilehto, J. (2003). Long-term improvement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study. Diabetes 52, 2532–8.CrossRefGoogle ScholarPubMed
Valencia, M. E., Bennett, P. H., Ravussin, E., Esparza, J., Fox, C. & Schulz, L. O. (1999). The Pima Indians in Sonora, Mexico. Nutr. Rev. 57, S55–7; discussion S57–8.Google ScholarPubMed
Van Gaal, L. F., Rissanen, A. M., Scheen, A. J., Ziegler, O. & Rossner, S. (2005). Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389–97.Google ScholarPubMed
Vanhaesebroeck, B., Ali, K., Bilancio, A., Geering, B. & Foukas, L. C. (2005). Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem. Sci. 30, 194–204.CrossRefGoogle ScholarPubMed
Vollenweider, P., Menard, B. & Nicod, P. (2002). Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance. Diabetes 51, 1052–9.CrossRefGoogle ScholarPubMed
Wallum, B. J., Taborsky, G. J. Jr., Porte, D. Jr.et al. (1987). Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J. Clin. Endocrinol. Metab. 64, 190–4.CrossRefGoogle ScholarPubMed
Weigle, D. S. (1994). Appetite and the regulation of body composition. FASEB J. 8, 302–10.CrossRefGoogle ScholarPubMed
Weigle, D. S., Bukowski, T. R., Foster, D. C.et al. (1995). Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J. Clin. Invest. 96, 2065–70.CrossRefGoogle ScholarPubMed
Willett, W. C., Dietz, W. H. & Colditz, G. A. (1999). Guidelines for healthy weight. N. Engl. J. Med. 341, 427–34.CrossRefGoogle ScholarPubMed
Wilson, B. E., Meyer, G. E., Cleveland, J. C. Jr. & Weigle, D. S. (1990). Identification of candidate genes for a factor regulating body weight in primates. Am. J. Physiol. 259, 1148–55.Google ScholarPubMed
Wolkow, C. A., Kimura, K. D., Lee, M. S. & Ruvkun, G. (2000). Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290, 147–50.CrossRefGoogle Scholar
Wolkow, C. A., Munoz, M. J., Riddle, D. L. & Ruvkun, G. (2002). Insulin receptor substrate and p55 orthologous adaptor proteins function in the Caenorhabditis elegans daf-2/insulin-like signaling pathway. J. Biol. Chem. 277, 49 591–7.CrossRefGoogle ScholarPubMed
Woods, S. C. & Porte, D. Jr. (1977). Relationship between plasma and cerebrospinal fluid insulin levels of dogs. Am. J. Physiol. 233, E331–4.Google ScholarPubMed
Woods, S. C. & Porte, D. Jr. (1978). The central nervous system, pancreatic hormones, feeding, and obesity. Adv. Metab. Disord. 9, 283–312.CrossRefGoogle ScholarPubMed
Woods, S. C. & Seeley, R. J. (2001). Insulin as an adiposity signal. Int. J. Obes. Relat. Metab. Disord. 25 Suppl. 5, S35–8.CrossRefGoogle ScholarPubMed
Woods, S. C., Lotter, E. C., McKay, L. D. & Porte, D. Jr. (1979). Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–5.CrossRefGoogle ScholarPubMed
Woods, S. C., Seeley, R. J., Rushing, P. A., D'Alessio, D. & Tso, P. (2003). A controlled high-fat diet induces an obese syndrome in rats. J. Nutr. 133, 1081–7.CrossRefGoogle ScholarPubMed
Xu, A. W., Kaelin, C. B., Takeda, K., Akira, S., Schwartz, M. W. & Barsh, G. S. (2005). Phosphatidylinositol 3-kinase integrates the action of insulin and leptin on hypothalamic neurons. J. Clin. Invest. 115, 951–8.CrossRefGoogle Scholar
Yu, C., Chen, Y., Zong, H.et al. (2002). Mechanism by which fatty acids inhibit insulin activation of IRS-1 associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277, 50 230–6.CrossRefGoogle ScholarPubMed
Zabolotny, J. M., Bence-Hanulec, K. K., Stricker-Krongrad, A.et al. (2002). PTP1B regulates leptin signal transduction in vivo. Dev. Cell. 2, 489–95.CrossRefGoogle ScholarPubMed
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. & Friedman, J. M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–32.CrossRefGoogle ScholarPubMed
Zhao, A. Z., Shinohara, M. M., Huang, D.et al. (2000). Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J. Biol. Chem. 275, 11 348–54.CrossRefGoogle ScholarPubMed
Zhao, A. Z., Huan, J. N., Gupta, S., Pal, R. & Sahu, A. (2002). A phosphatidylinositol 3 kinase phosphodiesterase 3B cyclic AMP pathway in hypothalamic action of leptin on feeding. Nat. Neurosci. 5, 727–8.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org 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 saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ 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.

  • Leptin and insulin as adiposity signals
    • By Kevin D. Niswender, Diabetes, Endocrinology and Metabolism, 715, Preston Research Building, Vanderbilt University, Medical Center, 2220, Pierce Avenue Nashville, TN 37232–6303, USA
  • Edited by Jenni Harvey, University of Dundee, Dominic J. Withers, Imperial College of Science, Technology and Medicine, London
  • Book: Neurobiology of Obesity
  • Online publication: 15 September 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511541643.005
Available formats
×

Save book to Dropbox

To save content items to your account, please 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 account. Find out more about saving content to Dropbox.

  • Leptin and insulin as adiposity signals
    • By Kevin D. Niswender, Diabetes, Endocrinology and Metabolism, 715, Preston Research Building, Vanderbilt University, Medical Center, 2220, Pierce Avenue Nashville, TN 37232–6303, USA
  • Edited by Jenni Harvey, University of Dundee, Dominic J. Withers, Imperial College of Science, Technology and Medicine, London
  • Book: Neurobiology of Obesity
  • Online publication: 15 September 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511541643.005
Available formats
×

Save book to Google Drive

To save content items to your account, please 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 account. Find out more about saving content to Google Drive.

  • Leptin and insulin as adiposity signals
    • By Kevin D. Niswender, Diabetes, Endocrinology and Metabolism, 715, Preston Research Building, Vanderbilt University, Medical Center, 2220, Pierce Avenue Nashville, TN 37232–6303, USA
  • Edited by Jenni Harvey, University of Dundee, Dominic J. Withers, Imperial College of Science, Technology and Medicine, London
  • Book: Neurobiology of Obesity
  • Online publication: 15 September 2009
  • Chapter DOI: https://doi.org/10.1017/CBO9780511541643.005
Available formats
×