Activation of Stat3 Signaling in AgRP Neurons Promotes Locomotor Activity

Mesaros, Andrea; Koralov, Sergei B.; Rother, Eva; Wunderlich, Frank; Ernst, Marianne B.; Barsh, Gregory S.; Rajewsky, Klaus; Brüning, Jens C.

doi:10.1016/j.cmet.2008.01.007

Cited by 117 publications

(91 citation statements)

References 216 publications

(257 reference statements)

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“…The contribution of the melanocortin system to leptin effects on energy expenditure and body weight is supported by numerous pharmacological studies (98)(99)(100). A number of parallel genetic studies similarly demonstrated that locomotor activity, temperature, or energy expenditure are changed in mice with modified expression of OB-Rb or its signaling molecular partners in ARH neurons (17,20,55,79,101,102).…”

Section: Body Weight Body Weight Control Is Exceptionally Complicatedmentioning

confidence: 78%

Sixteen years and counting: an update on leptin in energy balance

Gautron¹,

Elmquist²

2011

J. Clin. Invest.

311

251

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Cloned in 1994, the ob gene encodes the protein hormone leptin, which is produced and secreted by white adipose tissue. Since its discovery, leptin has been found to have profound effects on behavior, metabolic rate, endocrine axes, and glucose fluxes. Leptin deficiency in mice and humans causes morbid obesity, diabetes, and various neuroendocrine anomalies, and replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure. Here, we provide an update on the most current understanding of leptin-sensitive neural pathways in terms of both anatomical organization and physiological roles. IntroductionThe nervous system regulates energy balance at the organismal level by constantly adjusting energy intake, expenditure, and storage. The influence of the nervous system over metabolic functions was first suggested at the beginning of the 20th century when excessive adiposity was associated with pituitary tumors and injury to the hypothalamus (1). However, it was not until the 1940s that selective surgical lesions of certain hypothalamic areas were found to result in extreme obesity or leanness in rats (2, 3). Over the last few decades, numerous discoveries substantially extended our understanding of the neural control of metabolism. However, it is safe to say that none were more important than the cloning of the ob gene by Friedman and colleagues in 1994 (4). The ob gene encodes the protein leptin, which is a hormone produced and secreted by the white adipose tissue, and consequently, its circulating levels are closely related to body fat mass (5, 6). Leptin deficiency in mice homozygous for a mutant ob gene (ob/ob mice) causes morbid obesity, diabetes, and various neuroendocrine anomalies, and leptin replacement leads to decreased food intake, normalized glucose homeostasis, and increased energy expenditure (7-10). Several splice variants of the leptin receptor have been identified, and the "short forms" are widely expressed in multiple tissues (11). The "long form" of the leptin receptor encodes a protein with a longer cytoplasmic domain (OB-Rb) that is highly expressed in particular sites within the CNS (refs. 10, 12, and Table 1). The short forms of the leptin receptor are also present within the CNS (11), but OB-Rb is sufficient for leptin actions on metabolism (13,14). OB-Rb is a type 1 cytokine receptor, which stimulates the JAK/STAT3 pathway (15) and PI3K (16,17). Leptin induces transcriptional changes of several genes via the JAK/STAT3 pathway, and rapid changes in cellular activity and membrane potential may underlie the acute actions of leptin (18). While actions of this hormone in peripheral tissues have been identified, studies in genetically modified mice have demonstrated that leptin action only in the CNS is sufficient to regulate body weight, feeding, energy expenditure, and glucose metabolism (13,(19)(20)(21).Since leptin is clearly not the only metabolic signal acting on the brain, the range of its effects on behavior, metabolism, and endocrinology is trul...

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Section: Body Weight Body Weight Control Is Exceptionally Complicatedmentioning

confidence: 78%

Sixteen years and counting: an update on leptin in energy balance

Gautron¹,

Elmquist²

2011

J. Clin. Invest.

311

251

View full text Add to dashboard Cite

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“…Body fat content was measured in vivo by NMR using a minispec mq7.5 (Bruker Optik) as previously described (38).…”

Section: Methodsmentioning

confidence: 99%

Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism

Belgardt

Mauer

Wunderlich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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145

183

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c-Jun N-terminal kinase (JNK) 1-dependent signaling plays a crucial role in the development of obesity-associated insulin resistance. Here we demonstrate that JNK activation not only occurs in peripheral tissues, but also in the hypothalamus and pituitary of obese mice. To resolve the importance of JNK1 signaling in the hypothalamic/pituitary circuitry, we have generated mice with a conditional inactivation of JNK1 in nestin-expressing cells (JNK1 ΔNES mice). JNK1 ΔNES mice exhibit improved insulin sensitivity both in the CNS and in peripheral tissues, improved glucose metabolism, as well as protection from hepatic steatosis and adipose tissue dysfunction upon high-fat feeding. Moreover, JNK1 ΔNES mice also show reduced somatic growth in the presence of reduced circulating growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations, as well as increased thyroid axis activity. Collectively, these experiments reveal an unexpected, critical role for hypothalamic/pituitary JNK1 signaling in the coordination of metabolic/endocrine homeostasis.brain | diabetes | obesity | inflammation | insulin resistance

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“…We have recently demonstrated that Stat3-C POMC mice showed a tendency toward reduced energy expenditure compared with controls, although this effect did not reach statistical significance (Mesaros et al, 2008). To further analyze the mechanism underlying the mild obesity observed in Stat3-C POMC mice, we directly measured food intake in these mice.…”

Section: Stat3-c Pomc Mice Exhibit Increased Food Intake and Decreasementioning

confidence: 99%