Disruption of the PIP3-phosphatase Pten in Pomc neurons results in diet-sensitive obesity

Abstract

Previous studies have suggested key roles for insulin and leptin as adiposity signals exerting modulatory functions at various CNS sites. The primary target of these hormones appears to be the hypothalamus, which comprises a tightly regulated and complex network of neuropeptides and neurotransmitters influencing parameters of energy homeostasis. Although the two hormones and their receptors are unrelated and structurally distinct, the cellular responses to insulin and leptin appear to converge at the level of the phosphatidylinositol 3-kinase (Pik3). In order to analyze the role of the Pik3 pathway in hypothalamic neurons, we used the Cre-loxP system to selectively disrupt the phosphatidylinositol-3,4,5-trisphosphate phosphatase Pten in Pomc-expressing neurons of the arcuate nucleus, a key hypothalamic area in the control of feeding behavior and energy homeostasis. As compared to wild type (WT) littermates, Pomc-specific Pten knockout (KO) males fed a normal chow diet (ND) display a significant increase in body weight (30.7±3.2 vs. 34.5±1.1g, p<0.001, at wk.14 in WT and KO, respectively). In contrast, females did not exhibit obesity under ND. However, under high fat diet (HFD), KO females developed marked obesity (26.0±2.7 vs. 34.5±4.9g, p<0.001) with increased epigonadal fat pad weights (1.6±1.0 vs. 3.6±1.5g, p<0.01), and elevated serum leptin levels (48.2±34.1 vs. 113.7±65.3 ng/ml, p<0.05, at wk.15 in WT and KO, respectively). Moreover, obesity in the KO mice fed the high fat diet was characterized by concomitant impaired glucose tolerance. However, monitoring of physical activity, food consumption, and metabolic performance did not result in significant differences between KO and WT mice. Quantitative gene expression analysis in hypothalamic tissues of WT an KO mice by TaqMan RT-PCR indicated that obesity developed despite unaltered expression of Pomc-mRNA. Taken together, these data provide in vivo evidence for an essential role of Pik3 signaling in Pomc neurons with respect to energy homeostasis.