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.

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    • "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). "
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    • "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. "
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    • "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). "
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