Expression of Peroxisome Proliferator-Activated Receptor-γ in Key Neuronal Subsets Regulating Glucose Metabolism and Energy Homeostasis

In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-gamma agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPAR gamma is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPAR gamma distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spanning the hypothalamus, the ventral tegmental area, and the nucleus tractus solitarius. In several brain areas, nuclear PPAR gamma immunoreactivity was detected in cells that costained for neuronal nuclei, a neuronal marker. In the hypothalamus, PPAR gamma immunoreactivity was observed in a majority of neurons in the arcuate (including both agouti related protein and alpha-MSH containing cells) and ventromedial hypothalamic nuclei and was also present in the hypothalamic paraventricular nucleus, the lateral hypothalamic area, and tyrosine hydroxylase-containing neurons in the ventral tegmental area but was not expressed in the nucleus tractus solitarius. To validate and extend these histochemical findings, we generated mice with neuron-specific PPAR gamma deletion using nestin cre-LoxP technology. Compared with littermate controls, neuron-specific PPAR gamma nockout mice exhibited dramatic reductions of both hypothalamic PPAR gamma mRNA levels and PPAR gamma immunoreactivity but showed no differences in food intake or body weight over a 4-wk study period. We conclude that: 1) PPAR gamma mRNA and protein are expressed in the hypothalamus, 2) neurons are the predominant source of PPAR gamma in the central nervous system, although it is likely expressed by nonneuronal cell types as well, and 3) arcuate nucleus neurons that control energy homeostasis and glucose metabolism are among those in which PPAR gamma is expressed. (Endocrinology 150: 707-712, 2009)