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. 2007 Jun 21;583(Pt 2):437–443. doi: 10.1113/jphysiol.2007.135590

Hypothalamic leptin regulation of energy homeostasis and glucose metabolism

Gregory J Morton 1
PMCID: PMC2277030  PMID: 17584844

Abstract

Growing evidence suggests that food intake, energy expenditure and endogenous glucose production are regulated by hypothalamic areas that respond to a variety of peripheral signals. Therefore, in response to a reduction in energy stores or circulating nutrients, the brain initiates responses in order to promote positive energy balance to restore and maintain energy and glucose homeostasis. In contrast, in times of nutrient abundance and excess energy storage, key hypothalamic areas activate responses to promote negative energy balance (i.e. reduced food intake and increased energy expenditure) and decreased nutrient availability (reduced endogenous glucose production). Accordingly, impaired responses or ‘resistance’ to afferent input from these hormonal or nutrient-related signals would be predicted to favour weight gain and insulin resistance and may contribute to the development of obesity and type 2 diabetes.

The hypothalamus is a brain region thought to play a critical role in the regulation of energy homeostasis. Early support for a central role of the hypothalamus in feeding emerged from lesioning studies. Lesions of the ventromedial hypothalamus were shown to cause hyperphagia and obesity (Hetherington & Ranson, 1940) while lesions of the lateral hypothalamus caused reduced food intake and leanness (Anand & Brobeck, 1951). Since then, a large and compelling body of evidence, first hypothesized by Kennedy over 50 years ago (Kennedy, 1953), suggests that body adiposity is regulated by circulating factors that are released in proportion to body fat mass and act in the brain to maintain energy balance. Two hormones postulated to act as these ‘adiposity’ signals are insulin and leptin. Both hormones circulate at levels proportional to body fat (Bagdade et al. 1967; Considine et al. 1996) and interact with their respective receptors to regulate food intake and energy expenditure (Baskin et al. 1988, 1999). Central administration of either hormone reduces food intake and body weight (Woods et al. 1979; Campfield et al. 1995) while conversely, deficiency of either hormone results in hyperphagia (Zhang et al. 1994; Sipols et al. 1995). Recent evidence suggests, however, that in addition to playing a critical role in the regulation of energy homeostasis, insulin and leptin may also play an important role in the hypothalamic control of glucose metabolism (Fig. 1).

Figure 1. Model depicting the central control of energy homeostasis and glucose metabolism.

Figure 1

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Neuronal systems sense input from adiposity signals (e.g. insulin and leptin) and nutrient-related signals (FFAs) and activate responses to regulate food intake, energy expenditure and hepatic glucose production (adapted from Schwartz & Porte, 2005).

Hypothalamic insulin action and control of peripheral glucose metabolism

Well known for its effects on peripheral tissues, the pancreatic hormone insulin also regulates blood glucose levels through its action in the brain. Support for this assertion stems in part, from mice with neuron-specific deletion of either the insulin receptor or insulin receptor substrate-2 (IRS-2), an intracellular mediator of insulin signalling. These mice display a mildly obese, hyperphagic and insulin-resistant phenotype (Bruning et al. 2000; Kubota et al. 2004; Lin et al. 2004) establishing a requirement for neuronal insulin signalling in energy homeostasis and glucose metabolism. Furthermore, rescue of insulin receptor function selectively in liver and pancreatic beta-cells prevents the development of diabetes in insulin receptor-deficient mice when combined with concomitant expression of insulin receptor in brain (Okamoto et al. 2004). In rats, infusion of insulin into either the 3rd ventricle or directly into mediobasal hypothalamus (in the area of the arcuate nucleus (ARC)) reduces hepatic gluconeogenesis by increasing liver insulin sensitivity (Obici et al. 2002c). Intrahypothalamic insulin infusion also improves insulin sensitivity in mice (Inoue et al. 2006). Similarly, increasing hypothalamic phosphatidylinositol 3-kinase (PI3K, a major intracellular mediator of insulin action) signalling by overexpression of either IRS-2 (which links insulin receptors to PI3K) or the PI3K target, protein kinase B (PKB/Akt, an enzyme activated by PI3K) increases peripheral insulin sensitivity in rats with uncontrolled diabetes induced by streptozotocin (STZ-DM) (Gelling et al. 2006). Combined with evidence that both antisense ‘knockdown’ of insulin receptors in the area of the ARC and local infusion of a PI3K inhibitor cause peripheral insulin resistance in rats (Obici et al. 2002a, c; Gelling et al. 2006), these data collectively implicate insulin signalling in the CNS for the regulation of both body weight and glucose metabolism.

The mechanism by which insulin action in the brain lowers plasma glucose levels appears to involve activation of ATP-sensitive potassium (KATP) channels on ARC neurons (Obici et al. 2002c; Pocai et al. 2005a). This conclusion stems from studies in which the ability of either intracerebroventricular (i.c.v.) or systemic insulin administration to inhibit hepatic glucose production (GP) is prevented by selective administration of a KATP channel blocker (glybenclamide) into the ARC. Conversely, local infusion of a KATP channel opener into the ARC mimics the effect of insulin on endogenous GP, suggesting that circulating insulin inhibits GP, at least in part, via a mechanism that involves activation of hypothalamic KATP channels. Since the ability of insulin to suppress endogenous GP is impaired in mice lacking the sulphonylurea receptor 1 subunit (SUR1) (Pocai et al. 2005a), activation of KATP channels in the mediobasal hypothalamus appears to be both necessary and sufficient to explain the central effects of insulin on hepatic GP.

In addition to the ARC, the hypothalamic ventromedial nucleus (VMN) is implicated in the physiological control of both glucose metabolism and energy balance. Szabo and colleagues showed in the 1980s that microinjection of insulin into the VMN lowers blood glucose levels via an autonomic mechanism involving the vagus nerve (Iguchi et al. 1981). Subsequently, leptin administration into the VMN was shown to markedly increase glucose uptake into skeletal muscle and adipose tissue (Haque et al. 1999; Minokoshi et al. 1999), further implicating VMN neurons in the control of peripheral insulin action, and recent studies established that leptin signalling in VMN neurons is required for intact control of energy homeostasis (using Cre-loxP technology to delete leptin receptors from these cells) (Dhillon et al. 2006). The VMN is enriched in ‘glucose-sensing’ neurons (Song & Routh, 2005; Kang et al. 2006) that are essential for autonomic and hormonal responses to hypoglycaemia (McCrimmon et al. 2005; Tong et al. 2007) and this glucose-sensing function is dependent on KATP channel activation (McCrimmon et al. 2005), similar to the effects of both insulin and leptin on ARC neurons (Spanswick et al. 2000; Pocai et al. 2005a). Lastly, IRS-2 is concentrated in the VMN as well as in the ARC (Pardini et al. 2006) and insulin-mediated KATP channel activation is PI3K dependent in ARC neurons. Taken together, these observations support the hypothesis that, like the ARC, VMN neurons sense and integrate input from both hormonal (insulin, leptin) and nutrient-related (glucose) signals to regulate autonomic outflow, energy intake and peripheral insulin action via signal transduction mechanisms resembling those utilized by ARC neurons.

How a signal from the hypothalamus mediates changes in peripheral insulin sensitivity remains an active area of study. One hypothesis proposes a key role for communication between hypothalamus and hindbrain areas that control autonomic outflow to the liver and other tissues via the vagus nerve. Specifically, activation of descending projections from ARC neurons to the hindbrain is proposed to increase hepatic insulin sensitivity via activation of vagal efferent fibres supplying the liver (Fig. 2). This hypothesis is supported by evidence that hepatic branch vagotomy attenuates the suppression of GP following intrahypothalamic infusion of insulin, free fatty acids (FFAs) or a KATP channel opener, whereas there was no effect of selective vagal deafferentation (Pocai et al. 2005a, b). Whether additional mechanisms link hypothalamic nutrient and hormone sensing to the control of glucose metabolism in peripheral tissues is a key question that awaits further study.

Figure 2. Model of the hypothalamic regulation of hepatic glucose production.

Figure 2

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Both insulin activation of the IRS-PI3K pathway and increased concentration of LCFA-CoA levels in the ARC are proposed to activate second-order neurons that project to hindbrain areas. In response to this input, output of motor neurons of the vagus nerve that supply the liver is increased (adapted from Pocai et al. 2005b). ARC, arcuate nucleus; NTS, nucleus of the solitary tract; FFA, free fatty acids.

Hypothalamic leptin and glucose metabolism

Leptin binding to the ‘long’ or ‘signalling’ isoform of the leptin receptor, leprb, results in activation of Jak2 (Janus-Kinase), which in turn phosphorylates leprb, resulting in the recruitment and tyrosine phosphorylation of the transcription factor signal transducer and activation of transcription-3 (STAT3) (Howard & Flier, 2006). Phospho-STAT3 dimers then translocate to the nucleus and activate the transcription of various target genes including suppressor of cytokine signalling-3 (SOCS-3), a signalling inhibitor that blocks leprb activation of Jak-STAT signalling (Howard & Flier, 2006). Recent data suggest that like insulin, leptin is also capable of activating the IRS–PI3K pathway (Niswender et al. 2001; Niswender et al. 2003) and that this effect, like activation of the Jak-STAT pathway, is required for leptin regulation of food intake (Niswender et al. 2001). Therefore, hypothalamic PI3K signalling may play a critical role in leptin, as well as insulin, action on energy and glucose homeostasis.

Although changes of food intake and body adiposity can clearly affect insulin sensitivity in peripheral tissues, several observations suggest that leptin regulation of glucose homeostasis occurs independently of its effects on food intake. For example, impaired glucose metabolism characteristic of genetic models of leptin deficiency occurs regardless of whether the animals are obese (e.g. ob/ob mice) (Zhang et al. 1994) or lean (e.g. various models of lipodystrophy due to defective adipocyte development) (Shimomura et al. 1999), and leptin treatment corrects these metabolic abnormalities via a mechanism that cannot be explained by changes of food intake or body weight (Schwartz et al. 1996; Shimomura et al. 1999). Therefore, deficient leptin signalling appears to have severe consequences for glucose metabolism that are independent of, and additive to, its effects on energy intake or body fat content. Moreover, the brain is implicated as a key target for the glucose-lowering action of leptin, as i.c.v. administration of leptin rescues the insulin resistance and diabetes phenotype of lipodystrophic mice at doses that are ineffective when administered peripherally (Asilmaz et al. 2004). Thus, leptin signalling appears to be required for intact glucose metabolism, and recent evidence implicates the ARC as a key site mediating this effect.

Using a combination of gene targeting and viral gene therapy to rescue leptin receptors in the hypothalamus of mice that otherwise lack these receptors, Elmquist and colleagues found that while ARC-directed leptin receptor gene expression reduced food intake and body fat mass only modestly, it effectively normalized blood glucose and insulin levels (Coppari et al. 2005). Our recent work using Koletsky (fak/fak) rats that develop obesity, hyperphagia, glucose intolerance and insulin resistance due to genetic absence of all leptin-receptor protein (Takaya et al. 1996; Ernsberger et al. 1999) extends these findings. We found that restoring leptin receptors selectively to the ARC of Koletsky rats using an adenoviral gene therapy approach dramatically improved peripheral insulin sensitivity, even when the effects of food intake and body weight were prevented by pair-feeding (Morton et al. 2005). Reduced leptin signalling in the hypothalamus therefore contributes to impaired glucose metabolism in animals that lack a leptin signal. Furthermore, this response to ARC-directed leptin receptor gene therapy appears to depend, at least in part, on PI3K signalling, since it is attenuated by prior i.c.v. infusion of a PI3K inhibitor. Conversely, ARC-directed expression of a constitutively active mutant of PKB mimicked the insulin-sensitizing effect of restored hypothalamic leptin signalling in these animals (Morton et al. 2005). These findings suggest that hypothalamic leptin signalling is an important determinant of peripheral insulin sensitivity and that the underlying neuronal mechanism involves PI3K. This conclusion is further supported by studies of mice (s/s) in which the endogenous leptin receptor gene was replaced with a mutant allele that cannot signal via the Jak-Stat pathway, but otherwise functions normally (Bates et al. 2003, 2005). These animals develop severe hyperphagia and obesity, but unlike db/db mice, exhibit only mild disturbances of glucose homeostasis that can be prevented by caloric restriction (Bates et al. 2005). These results suggest that although leptin-receptor-mediated JAK-STAT signalling is essential for regulation of food intake and body weight, this is not the case for leptin regulation of glucose metabolism. Rather, leptin-stimulated PI3K signalling appears to mediate this effect.

The hypothalamic ARC contains distinct neuronal subsets that can potently regulate food intake, energy expenditure and insulin sensitivity. Two well characterized neuronal populations in this area express both insulin and leptin receptors, are regulated by both insulin and leptin, and exert opposing effects on energy balance and glucose metabolism. One of these subsets are neurons containing neuropeptide Y/agouti-related peptide (NPY/AgRP), peptides that potently stimulate food intake and reduce energy expenditure and these cells are inhibited by leptin and insulin. The other subset contains neurons that express the melanocortin precursor, pro-opiomelanocortin (POMC), which unlike NPY/AgRP neurons, are stimulated by input from leptin and act on melanocortin receptors (Mc3/4r) to reduce food intake (Schwartz & Porte, 2005). In addition to the release of NPY, NPY/AgRP neurons stimulate feeding by reducing melanocortin signalling via release of AgRP, an endogenous melanocortin 3/4 receptor antagonist (Ollmann et al. 1997; Shutter et al. 1997). In addition to these well characterized effects on energy balance, recent evidence suggests that both neuronal populations may also be important in the central regulation of glucose metabolism. For example, central administration of NPY causes insulin resistance even when its effects on food intake are prevented (Marks & Waite, 1997; van den Hoek et al. 2004), and similar responses are elicited following chronic i.c.v. infusions of the melanocortin 3/4 receptor antagonist, SHU9119 (Adage et al. 2001), while central infusion of the melanocortin receptor agonist, MTII, has the opposite effect (Obici et al. 2001). Collectively, these observations support the hypothesis that in addition to having potent effects on energy balance, ARC neurons also participate in the control of insulin sensitivity in peripheral tissues (Fig. 3). Since leptin-receptor gene therapy directed to the ARC reduces hypothalamic Npy mRNA levels (Morton et al. 2003), reduced signalling by NPY/AgRP neurons may contribute to the improvement of insulin sensitivity induced by hypothalamic leptin receptor gene therapy in our studies.

Figure 3. Model of the hypothalamic neurocircuits involved in glucose metabolism.

Figure 3

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Insulin and leptin act in the arcuate nucleus (ARC) to inhibit NPY/AgRP neurons and activate pro-opiomelanocortin (POMC) neurons. Both neuronal subsets project to other hypothalamic areas including the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA). Activation of neuronal projections from these hypothalamic neurons to hindbrain areas, such as the nucleus of the solitary tract (NTS), generates a vagal signal to the liver to regulate hepatic glucose production. 3V, third ventricle.

Nutrient-related signals

The CNS is thought to sense and respond not only to input from adiposity signals such as insulin and leptin, but also to nutrient-related signals. One putative hypothalamic signal of nutrient availability is the intracellular accumulation of long-chain fatty acyl-CoA (LCFA-CoA) molecules. Consistent with this hypothesis, both i.c.v. administration of the monounsaturated FFA, oleic acid, and local inhibition of lipid oxidation due to increased malonyl CoA levels (either using a fatty acid synthase (FAS) inhibitor or an inhibitor of carnitine palmitoyl-transferase-1 (CPT-1), a key regulator of β-oxidation), decreases both food intake and GP (Loftus et al. 2000; Obici et al. 2002b; Lam et al. 2005). Conversely, hypothalamic reduction of LCFA-CoA levels by local infusion of adeno-associated virus expressing malonyl coenzyme A decarboxylase (MCD, an enzyme responsible for malonyl CoA degradation), causes obesity and insulin resistance in rats (He et al. 2006). These effects of FFA on hepatic GP appear to mimic the effect of central insulin on peripheral insulin sensitivity, and the mechanism is similarly suggested to require central activation of KATP channels and increased vagal outflow to the liver (Pocai et al. 2005b).

In contrast to LCFA-CoA, the enzyme AMP-activated protein kinase (AMPK) is a fuel sensor that is activated in response to depletion of cellular ATP. Besides its role in the periphery, hypothalamic AMPK is thought to play an important role in control of energy balance. Activation of hypothalamic AMPK stimulates food intake and body weight while, conversely, suppression of its activity has the opposite effect (Minokoshi et al. 2004). Moreover, hypothalamic AMPK activity is inhibited by central administration of glucose, insulin and leptin, as well as by physiological conditions such as re-feeding, while it is activated by interventions that stimulate food intake including i.c.v. ghrelin or fasting (Xue & Kahn, 2006). These data support the hypothesis that fuel sensors in the hypothalamus respond to changes in circulating nutrients and play a key role in the regulation of both energy homeostasis and glucose metabolism.

Conclusions

Based on the current literature, an emerging model suggests that when confronted with reduced nutrient availability, there is an adaptive, hypothalamic response that increases hepatic GP to meet the metabolic needs of the body. This metabolic response occurs in parallel with hypothalamic responses that stimulate food intake, and it appears to involve similar peripheral circulating factors, signal transduction molecules and neurocircuitry as those implicated in energy homeostasis. This is an important concept, as insulin resistance in peripheral tissues is common in obesity and type 2 diabetes, and the mechanism underlying this resistance involves impaired activation of PI3K. Since convergent signal transduction (e.g. via the IRS-PI3K signalling pathway) and termination (e.g. SOCS-3) mechanisms mediate neuronal actions of insulin and leptin, defects within a single biochemical pathway can potentially cause resistance to the central actions of both hormones. This, in turn, can be predicted to induce hyperphagia, weight gain, hepatic insulin resistance and glucose intolerance. This model is supported by evidence that both heterozygous SOCS-3-deficient mice and neuronal cell-specific SOCS-3 conditional knockout mice display increased leptin sensitivity, and are protected against the development of obesity on a high fat diet (Howard et al. 2004; Mori et al. 2004). Thus, neuronal SOCS-3 (which can disrupt signalling via both the JAK-Stat and PI3K signalling pathways) appears to play a physiological role to favour positive energy balance and weight gain by limiting the hypothalamic response to input from adiposity-related hormones. This model is further supported from evidence that diet-induced obesity is associated with impaired behavioural and hypothalamic responses to insulin, leptin and FFA (El-Haschimi et al. 2000; Morgan et al. 2004; De Souza et al. 2005). Taken together, these findings indicate that reduced hypothalamic input from adiposity- and nutrient-related signals occurs in common forms of obesity and are sufficient to impair both energy homeostasis and glucose metabolism. Whether such defects cause or are associated with the development of obesity, insulin resistance and diabetes in humans is an important scientific question.

Acknowledgments

The author thanks Michael W. Schwartz (University of Washington) for helpful discussion and advice. G.J.M. was funded by the Clinical Nutrition Research Unit and Diabetes Endocrinology Research Center of the University of Washington

References

  1. Adage T, Scheurink AJ, de Boer SF, de Vries K, Konsman JP, Kuipers F, et al. Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats. J Neurosci. 2001;21:3639–3645. doi: 10.1523/JNEUROSCI.21-10-03639.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anand BK, Brobeck JR. Localization of a ‘feeding centre’ in the hypothalamus of the rat. Procedings Soc for Exp Biol Med. 1951;77:323–324. doi: 10.3181/00379727-77-18766. [DOI] [PubMed] [Google Scholar]
  3. Asilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki K, Fayzikhodjaeva G, et al. Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest. 2004;113:414–424. doi: 10.1172/JCI19511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bagdade JD, Bierman EL, Porte D., Jr The significance of basal insulin levels in the evaluation of the insulin response to glucose in diabetic and nondiabetic subjects. J Clin Invest. 1967;46:1549–1557. doi: 10.1172/JCI105646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baskin DG, Breininger JF, Schwartz MW. Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes. 1999;48:828–833. doi: 10.2337/diabetes.48.4.828. [DOI] [PubMed] [Google Scholar]
  6. Baskin DG, Wilcox BJ, Figlewicz DP, Dorsa DM. Insulin and insulin-like growth factors in the CNS. Trends Neurosci. 1988;11:107–111. doi: 10.1016/0166-2236(88)90155-5. [DOI] [PubMed] [Google Scholar]
  7. Bates SH, Kulkarni RN, Seifert M, Myers MG., Jr Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metabolism. 2005;1:169–178. doi: 10.1016/j.cmet.2005.02.001. [DOI] [PubMed] [Google Scholar]
  8. Bates SH, Stearns WH, Dundon TA, Schubert M, Tso AW, Wang Y, et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature. 2003;421:856–859. doi: 10.1038/nature01388. [DOI] [PubMed] [Google Scholar]
  9. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289:2122–2125. doi: 10.1126/science.289.5487.2122. [DOI] [PubMed] [Google Scholar]
  10. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995;269:546–549. doi: 10.1126/science.7624778. [DOI] [PubMed] [Google Scholar]
  11. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292–295. doi: 10.1056/NEJM199602013340503. [DOI] [PubMed] [Google Scholar]
  12. Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, et al. The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metabolism. 2005;1:63–72. doi: 10.1016/j.cmet.2004.12.004. [DOI] [PubMed] [Google Scholar]
  13. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005;146:4192–4199. doi: 10.1210/en.2004-1520. [DOI] [PubMed] [Google Scholar]
  14. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V, et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron. 2006;49:191–203. doi: 10.1016/j.neuron.2005.12.021. [DOI] [PubMed] [Google Scholar]
  15. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest. 2000;105:1827–1832. doi: 10.1172/JCI9842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ernsberger P, Koletsky RJ, Friedman JE. Molecular pathology in the obese spontaneous hypertensive Koletsky rat: a model of syndrome X. Ann N Y Acad Sci. 1999;892:272–288. doi: 10.1111/j.1749-6632.1999.tb07801.x. [DOI] [PubMed] [Google Scholar]
  17. Gelling RW, Morton GJ, Morrison CD, Niswender KD, Myers MG, Jr, Rhodes CJ, Schwartz MW. Insulin action in the brain contributes to glucose lowering during insulin treatment of diabetes. Cell Metab. 2006;3:67–73. doi: 10.1016/j.cmet.2005.11.013. [DOI] [PubMed] [Google Scholar]
  18. Haque MS, Minokoshi Y, Hamai M, Iwai M, Horiuchi M, Shimazu T. Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats. Diabetes. 1999;48:1706–1712. doi: 10.2337/diabetes.48.9.1706. [DOI] [PubMed] [Google Scholar]
  19. He W, Lam TK, Obici S, Rossetti L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci. 2006;9:227–233. doi: 10.1038/nn1626. [DOI] [PubMed] [Google Scholar]
  20. Hetherington A, Ranson SW. Hypothalamic lesions and adiposity in the rat. Anat Record. 1940;78:149–172. [Google Scholar]
  21. Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C, Flier JS. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med. 2004;10:734–738. doi: 10.1038/nm1072. [DOI] [PubMed] [Google Scholar]
  22. Howard JK, Flier JS. Attenuation of leptin and insulin signaling by SOCS proteins. Trends Endocrinol Metab. 2006;17:365–371. doi: 10.1016/j.tem.2006.09.007. [DOI] [PubMed] [Google Scholar]
  23. Iguchi A, Burleson PD, Szabo AJ. Decrease in plasma glucose concentration after microinjection of insulin into VMN. Am J Physiol Endocrinol Metab. 1981;240:E95–E100. doi: 10.1152/ajpendo.1981.240.2.E95. [DOI] [PubMed] [Google Scholar]
  24. Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, et al. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab. 2006;3:267–275. doi: 10.1016/j.cmet.2006.02.009. [DOI] [PubMed] [Google Scholar]
  25. Kang L, Dunn-Meynell AA, Routh VH, Gaspers LD, Nagata Y, Nishimura T, et al. Glucokinase is a critical regulator of ventromedial hypothalamic neuronal glucosensing. Diabetes. 2006;55:412–420. doi: 10.2337/diabetes.55.02.06.db05-1229. [DOI] [PubMed] [Google Scholar]
  26. Kennedy G. The role of depot fat in the hypothalamic control of food intake in the rat. Proc R Soc Lond B Biol Sci. 1953;140:578–592. doi: 10.1098/rspb.1953.0009. [DOI] [PubMed] [Google Scholar]
  27. Kubota N, Terauchi Y, Tobe K, Yano W, Suzuki R, Ueki K, et al. Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J Clin Invest. 2004;114:917–927. doi: 10.1172/JCI21484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lam TK, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L, Schwartz GJ, Rossetti L. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005;11:320–327. doi: 10.1038/nm1201. [DOI] [PubMed] [Google Scholar]
  29. Lin X, Taguchi A, Park S, Kushner JA, Li F, Li Y, White MF. Dysregulation of insulin receptor substrate 2 in beta cells and brain causes obesity and diabetes. J Clin Invest. 2004;114:908–916. doi: 10.1172/JCI22217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kuhajda FP. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science. 2000;288:2379–2381. doi: 10.1126/science.288.5475.2379. [DOI] [PubMed] [Google Scholar]
  31. McCrimmon RJ, Evans ML, Fan X, McNay EC, Chan O, Ding Y, Zhu W, Gram DX, Sherwin RS. Activation of ATP-sensitive K+ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats. Diabetes. 2005;54:3169–3174. doi: 10.2337/diabetes.54.11.3169. [DOI] [PubMed] [Google Scholar]
  32. Marks JL, Waite K. Intracerebroventricular neuropeptide Y acutely influences glucose metabolism and insulin sensitivity in the rat. J Neuroendocrinol. 1997;9:99–103. doi: 10.1046/j.1365-2826.1997.00554.x. [DOI] [PubMed] [Google Scholar]
  33. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–574. doi: 10.1038/nature02440. [DOI] [PubMed] [Google Scholar]
  34. Minokoshi Y, Haque MS, Shimazu T. Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes. 1999;48:287–291. doi: 10.2337/diabetes.48.2.287. [DOI] [PubMed] [Google Scholar]
  35. Morgan K, Obici S, Rossetti L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J Biol Chem. 2004;279:31139–31148. doi: 10.1074/jbc.M400458200. [DOI] [PubMed] [Google Scholar]
  36. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med. 2004;10:739–743. doi: 10.1038/nm1071. [DOI] [PubMed] [Google Scholar]
  37. Morton GJ, Gelling RW, Niswender KD, Morrison CD, Rhodes CJ, Schwartz MW. Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab. 2005;2:411–420. doi: 10.1016/j.cmet.2005.10.009. [DOI] [PubMed] [Google Scholar]
  38. Morton GJ, Niswender KD, Rhodes CJ, Myers MG, Jr, Blevins JE, Baskin DG, Schwartz MW. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fak/fak) rats. Endocrinology. 2003;144:2016–2024. doi: 10.1210/en.2002-0115. [DOI] [PubMed] [Google Scholar]
  39. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers MG, Jr, Seeley RJ, Schwartz MW. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes. 2003;52:227–231. doi: 10.2337/diabetes.52.2.227. [DOI] [PubMed] [Google Scholar]
  40. Niswender KD, Morton GJ, Stearns WH, Rhodes CJ, Myers MG, Jr, Schwartz MW. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature. 2001;413:794–795. doi: 10.1038/35101657. [DOI] [PubMed] [Google Scholar]
  41. Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. 2002a;5:566–572. doi: 10.1038/nn0602-861. [DOI] [PubMed] [Google Scholar]
  42. Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes. 2002b;51:271–275. doi: 10.2337/diabetes.51.2.271. [DOI] [PubMed] [Google Scholar]
  43. Obici S, Feng Z, Tan J, Liu L, Karkanias G, Rossetti L. Central melanocortin receptors regulate insulin action. J Clin Invest. 2001;108:1079–1085. doi: 10.1172/JCI12954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. 2002c;8:1376–1382. doi: 10.1038/nm1202-798. [DOI] [PubMed] [Google Scholar]
  45. Okamoto H, Nakae J, Kitamura T, Park BC, Dragatsis I, Accili D. Transgenic rescue of insulin receptor-deficient mice. J Clin Invest. 2004;114:214–223. doi: 10.1172/JCI21645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science. 1997;278:135–138. doi: 10.1126/science.278.5335.135. [DOI] [PubMed] [Google Scholar]
  47. Pardini AW, Nguyen HT, Figlewicz DP, Baskin DG, Williams DL, Kim F, Schwartz MW. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res. 2006;1112:169–178. doi: 10.1016/j.brainres.2006.06.109. [DOI] [PubMed] [Google Scholar]
  48. Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L, Rossetti L. Hypothalamic KATP channels control hepatic glucose production. Nature. 2005a;434:1026–1031. doi: 10.1038/nature03439. [DOI] [PubMed] [Google Scholar]
  49. Pocai A, Obici S, Schwartz GJ, Rossetti L. A brain-liver circuit regulates glucose homeostasis. Cell Metabolism. 2005b;1:53–61. doi: 10.1016/j.cmet.2004.11.001. [DOI] [PubMed] [Google Scholar]
  50. Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, et al. Specificity of leptin action on elevated blood glucose levels and hypothalmic neuropeptide Y gene expression in ob/ob mice. Diabetes. 1996;45:531–535. doi: 10.2337/diab.45.4.531. [DOI] [PubMed] [Google Scholar]
  51. Schwartz MW, Porte D., Jr Diabetes, obesity, and the brain. Science. 2005;307:375–379. doi: 10.1126/science.1104344. [DOI] [PubMed] [Google Scholar]
  52. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 1999;401:73–76. doi: 10.1038/43448. [DOI] [PubMed] [Google Scholar]
  53. Shutter JR, Graham M, Kinsey AC, Scully S, Luthy R, Stark KL. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 1997;11:593–602. doi: 10.1101/gad.11.5.593. [DOI] [PubMed] [Google Scholar]
  54. Sipols AJ, Baskin DG, Schwartz MW. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes. 1995;44:147–151. doi: 10.2337/diab.44.2.147. [DOI] [PubMed] [Google Scholar]
  55. Song Z, Routh VH. Differential effects of glucose and lactate on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes. 2005;54:15–22. doi: 10.2337/diabetes.54.1.15. [DOI] [PubMed] [Google Scholar]
  56. Spanswick D, Smith MA, Mirshamsi S, Routh VH, Ashford ML. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat Neurosci. 2000;3:757–758. doi: 10.1038/77660. [DOI] [PubMed] [Google Scholar]
  57. Takaya K, Ogawa Y, Hiraoka J, Hosoda K, Yamori Y, Nakao K, Koletsky RJ. Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat Genet. 1996;14:130–131. doi: 10.1038/ng1096-130. [DOI] [PubMed] [Google Scholar]
  58. Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B, Kramer MD, et al. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab. 2007;5:383–393. doi: 10.1016/j.cmet.2007.04.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. van den Hoek AM, Voshol PJ, Karnekamp BN, Buijs RM, Romijn JA, Havekes LM, Pijl H. Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes. 2004;53:2529–2534. doi: 10.2337/diabetes.53.10.2529. [DOI] [PubMed] [Google Scholar]
  60. Woods SC, Lotter EC, McKay LD, Porte D., Jr Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282:503–505. doi: 10.1038/282503a0. [DOI] [PubMed] [Google Scholar]
  61. Xue B, Kahn BB. AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. J Physiol. 2006;574:73–83. doi: 10.1113/jphysiol.2006.113217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]

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