Inactivation of Signal Transducer and Activator of Transcription 3 in Proopiomelanocortin (Pomc) Neurons Causes Decreased Pomc Expression, Mild Obesity, and Defects in Compensatory Refeeding

Department of Pediatrics , Stanford University, Palo Alto, California, United States
Endocrinology (Impact Factor: 4.5). 02/2007; 148(1):72-80. DOI: 10.1210/en.2006-1119
Source: PubMed


Leptin is an adipocyte-derived hormone that signals body energy status to the brain by acting on multiple neuronal subgroups in the hypothalamus, including those that express proopiomelanocortin (Pomc) and agouti-related protein (Agrp). Signal transducer and activator of transcription 3 (Stat3) is an important intracellular signaling molecule activated by leptin, and previous studies have shown that mice carrying a mutated leptin receptor that abolished Stat3 binding are grossly obese. To determine the extent to which Stat3 signaling in Pomc neurons was responsible for these effects, we constructed Pomc-specific Stat3 mutants using a Cre recombinase transgene driven by the Pomc promoter. We find that Pomc expression is diminished in the mutant mice, suggesting that Stat3 is required for Pomc transcription. Pomc-specific Stat3 female mutant mice exhibit a 2-fold increase in fat pad mass but only a slight increase in total body weight. Mutant mice remain responsive to leptin-induced hypophagia and are not hypersensitive to a high-fat diet; however, mutant mice fail to mount a normal compensatory refeeding response. These results demonstrate a requirement for Stat3 in transcriptional regulation of Pomc but indicate that this circuit is only one of several components that underlie the neuronal response to leptin and the role of Stat3 in that response.

Full-text preview

Available from:
  • Source
    • "Inactivation of the STAT3 pathway in POMC and AgRP neurons results in decreased pomc mRNA expression and agrp mRNA expression respectively (Bates et al., 2004; Mesaros et al., 2008; Xu et al., 2007). An additional imperative pathway of leptin action is the phos- phatidylinositol-3-kinase (PI3K) signaling pathway, which is also insulin's predominant intracellular signaling cascade (Niswender et al., 2001). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of obesity and its related disorders are increasing at a rate of pandemic proportions. Understanding the mechanisms behind the maintenance of energy balance is fundamental in developing treatments for clinical syndromes including obesity and diabetes. A neural network located in the the nucleus of the solitary tract-area postrema complex in the hindbrain and the hypothalamus in the forebrain has long been implicated in the control of energy balance. In the hypothalamus this central neuronal network consists of small populations of nuclei with distinct functions such as the arcuate nucleus (ARH), the paraventricular nuclei of the hypothalamus (PVH), the dorsomedial (DMH), the ventromedial (VMH) and the lateral hypothalamus (LH). These hypothalamic areas form interconnected neuronal circuits that respond to fluctuations in energy status by altering the expression of neuropeptides, leading to changes in energy intake and expenditure. Regulation of these hypothalamic nuclei involves the actions of orexigenic peptides (ie ghrelin), which act to stimulate energy intake and decrease energy expenditure, and anorexigenic peptides (ie. leptin and insulin), which act to reduce energy intake and stimulate energy expenditure. Here we review the role of the ARH, DMH and PVH in the control of energy homeostasis and how recent advances in research technologies (Cre-loxP technology, optogenetics and pharmacogenetics) have shed light on the role of these hypothalamic nuclei in the control of energy balance. Such novel findings include the implication of ARH POMC and AgRP neurons in the browning of white adipose tissue to regulate energy expenditure as well as the likely existence of divergent hypothalamic pathways in the DMH and PVH in the control of food intake and energy expenditure. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Full-text · Article · Aug 2015 · Molecular and Cellular Endocrinology
  • Source
    • "We used a model in which a mouse was globally deficient for the P85β regulatory subunit and the P85α regulatory subunit was selectively deleted from POMC neurons in a Credependent manner. These animals differed from those with a selective STAT3 deletion in POMC cells such that animals which lacked PI3K in POMC neurons had normal body weights food intake and glucose levels (Xu et al., 2007). However these animals failed to suppress food intake in response to acute leptin administration. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the past century, prevalent models of energy and glucose homeostasis have been developed from a better understanding of the neural circuits underlying obesity and diabetes. From the early hypothalamic lesion reports to the more recent pharmacological and molecular/genetic studies, the hypothalamic melanocortin system has been shown to play a critical role in the regulation of metabolism. This review attempts to highlight contributions to our current understanding of how numerous neuromodulators (leptin, insulin, and serotonin) integrate with the central melanocortin system to coordinate alterations in energy and glucose balance.
    Full-text · Article · Jun 2011 · European journal of pharmacology
  • Source
    • "Functional LepRs have recently been found on approximately 25–40% of POMC/CART neurons in the mediobasal hypothalamus using electrophysiology and immunohistochemistry (Williams et al., 2009). Similar percentages of POMC neurons display immunoreactive pStat3 following leptin treatment (~40%) (Xu et al., 2007). While leptin-induced excitation is seen throughout the retrochiasmatic area (RCA) and ARC, a higher percentage (40–70%) of leptin-excited POMC cells exist in the lateral RCA and medial ARC (Hill, 2010; Williams et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Circulating leptin and insulin convey information regarding energy stores to the central nervous system, particularly the hypothalamus. Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy balance and glucose homeostasis and express leptin and insulin receptors. However, the physiological significance of concomitant leptin and insulin action on POMC neurons remains to be established. Here, we show that mice lacking both leptin and insulin receptors in POMC neurons (Pomc-Cre, Lepr(flox/flox) IR(flox/flox) mice) display systemic insulin resistance, which is distinct from the single deletion of either receptor. In addition, Pomc-Cre, Lepr(flox/flox) IR(flox/flox) female mice display elevated serum testosterone levels and ovarian abnormalities, resulting in reduced fertility. We conclude that direct action of insulin and leptin on POMC neurons is required to maintain normal glucose homeostasis and reproductive function.
    Full-text · Article · Apr 2010 · Cell metabolism
Show more