Neuron-specific deletion of peroxisome proliferator-activated receptor delta (PPAR?) in mice leads to increased susceptibility to diet-induced obesity.

ABSTRACT: Central nervous system (CNS) lipid accumulation, inflammation and resistance to adipo-regulatory hormones, such as insulin and leptin, are implicated in the pathogenesis of diet-induced obesity (DIO). Peroxisome proliferator-activated receptors (PPAR ?, ?, ?) are nuclear transcription factors that act as environmental fatty acid sensors and regulate genes involved in lipid metabolism and inflammation in response to dietary and endogenous fatty acid ligands. All three PPAR isoforms are expressed in the CNS at different levels. Recent evidence suggests that activation of CNS PPAR? and/or PPAR? may contribute to weight gain and obesity. PPAR? is the most abundant isoform in the CNS and is enriched in the hypothalamus, a region of the brain involved in energy homeostasis regulation. Because in peripheral tissues, expression of PPAR? increases lipid oxidative genes and opposes inflammation, we hypothesized that CNS PPAR? protects against the development of DIO. Indeed, genetic neuronal deletion using Nes-Cre loxP technology led to elevated fat mass and decreased lean mass on low-fat diet (LFD), accompanied by leptin resistance and hypothalamic inflammation. Impaired regulation of neuropeptide expression, as well as uncoupling protein 2, and abnormal responses to a metabolic challenge, such as fasting, also occur in the absence of neuronal PPAR?. Consistent with our hypothesis, KO mice gain significantly more fat mass on a high-fat diet (HFD), yet are surprisingly resistant to diet-induced elevations in CNS inflammation and lipid accumulation. We detected evidence of upregulation of PPAR? and target genes of both PPAR? and PPAR?, as well as genes of fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPAR? in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression.

SUBMITTER: Kocalis HE 

PROVIDER: S-EPMC3423438 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature