In this study, we developed a transgenic mouse model to moderately upregulate Socs3 in POMC or leptin receptor neurons. We show that Socs3 upregulation alone in POMC neurons is sufficient to cause leptin resistance and obesity. In contrast, the lack of obesity in LepRb-Socs3-OE mice was unexpected. Several possible mechanisms exist to explain this paradox. First, Socs3 may exert different functions in different leptin receptor neurons. For example, deletion of LepRb from POMC or SF1 neurons results in a similar increase in body weight (30
). However, deletion of Socs3 gene from POMC neurons results in resistance to diet-induced obesity, whereas deletion of Socs3 in SF1 neurons affects glucose homeostasis but not body weight (13
). Alternatively, Socs3 may regulate energy balance in a leptin-independent way. It has been shown that cytokine expression increases in diet-induced obesity, and neuroinflammation may play an important role in the etiology of diet-induced obesity (33
). Thus, upregulation of Socs3 could diminish cytokine signaling in specific neuronal subtypes, thereby reducing neuroinflammation and mitigating weight gain. Finally, compensatory mechanisms may have developed in the LepRb-Socs3-OE mice, thus masking the development of obesity. We have detected increased expression of STAT3 protein in the hypothalamus of the LepRb-Socs3-OE mice, suggesting that this may represent a compensatory mechanism to counter the negative effect of Socs3 upregulation on STAT3 signaling. At present, the mechanism underlying increased STAT3 expression is unclear. It has been shown that leptin-deficient ob/ob
mice, which are obese, have reduced Stat3 expression in the hypothalamus, although the underlying molecular mechanism has not been elucidated (37
). mTOR has been shown to regulate STAT3 protein expression in breast cancer cell lines (38
), and we show here that Socs3 regulates mTOR-S6 signaling pathway in POMC neurons. However, regulation of mTOR-S6 signaling is complex in that mTOR activities in different hypothalamic neurons are differentially regulated by leptin (39
). Thus, it is possible that Socs3 upregulation could differentially regulate mTOR activity in a cell type–specific manner, which in turn affects STAT3 expression in discrete cell populations. However, it is equally possible that altered Stat3 expression in the hypothalamus is a secondary effect of altered whole-body physiology.
It is intriguing that upregulation of Socs3 in POMC neurons results in leptin resistance and obesity. Among all the brain regions that express leptin receptor, the arcuate nucleus is uniquely situated next to the median eminence, a circumventricular organ with an incomplete blood-brain barrier. Neurons located within the arcuate have direct contact with circulating leptin, and can respond more rapidly and sensitively (40
). Because of their constant communication with leptin, insulin, fatty acids, cytokines, and other inflammatory molecules, all of which would modulate Socs3 expression, POMC neurons likely experience regular dynamic changes in Socs3 expression. In contrast, Socs3 expression in other brain regions is normally low, and any elevation may be perceived as pathologic, which could trigger compensatory regulation. Consistent with this notion, diet-induced Socs3 upregulation as well as leptin resistance are observed primarily in the arcuate but not other hypothalamic sites (8
). Taken together, our results suggest that POMC neurons play an important role in mediating Socs3's effects on leptin resistance and obesity. Although no data are available to address whether Socs3 is upregulated in a cell type–specific fashion during the development of obesity, our study does not exclude the possibility that Socs3 upregulation in certain subsets of LepRb neurons or in non–LepRb-expressing cells contributes to obesity. It is also possible that the concerted action of multiple negative regulators of leptin signaling is required for development of severe obesity. In addition, low levels of leptin receptor are present in some peripheral tissues, although the importance of peripheral leptin action in energy balance remains controversial (41
). Because minimal Cre-mediated recombination is detected in peripheral tissues of LepRb-Cre mice, our current data could not address the contribution of peripheral Socs3 expression to diet-induced obesity.
Diet-induced leptin resistance manifests as reduced leptin signaling in hypothalamic neurons, but the timing of downregulation of different pathways is controversial. It has been shown that leptin-induced pSTAT3 is reduced in the arcuate nucleus after 6 days of high-fat feeding (8
). However, in other studies, leptin-induced phosphatidylinositol 3 kinase and mTOR signaling is impaired prior to defects in pSTAT3 signaling (9
). Although some of these discrepancies may be due to differences in diet composition, age, genetic background, housing condition, or dose and time course of leptin, these studies suggest that downregulation of a specific signaling pathway may trigger functional leptin resistance and obesity, which in turn causes downregulation of other leptin signaling pathways. We show that upregulation of Socs3 in POMC neurons inhibits pSTAT3 and mTOR pathways concurrently, which precedes the onset of weight gain. Thus, Socs3 may induce leptin resistance and obesity by downregulating multiple leptin pathways concomitantly. It has been shown that different leptin signaling pathways mediate specific subsets of leptin functions, such as energy balance, glucose homeostasis, growth, reproduction, and immunity (5
). Thus, downregulation of multiple leptin signaling pathways by Socs3 could effectively inhibit these leptin functions, most of which are impaired in diet-induced obesity. In summary, our study establishes a causal role for Socs3 in leptin resistance and obesity, and elucidates its underlying signaling mechanisms. In light of the current obesity epidemic, this study sheds light on the etiology of diet-induced leptin resistance and obesity in humans.