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 α, δ, γ) 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 PPARα and/or PPARγ may contribute to weight gain and obesity. PPARδ 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 PPARδ increases lipid oxidative genes and opposes inflammation, we hypothesized that CNS PPARδ 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 PPARδ. 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 PPARγ and target genes of both PPARα and PPARγ, as well as genes of fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPARδ in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression.
Highlights
Obesity is a serious health problem in the United States and worldwide [1,2]
Heterozygous (Het) and homozygous neuronal Peroxisome proliferator-activated receptor d (PPARd) knockout (KO) mice were born at the expected Mendelian ratios, were fertile and had no apparent developmental abnormalities compared to floxed littermate (f/f) control mice
PPARd mRNA expression in hypothalamus was reduced in a gene dosage dependent manner (Fig. 1A), but was not altered in peripheral tissues
Summary
Obesity is a serious health problem in the United States and worldwide [1,2]. Evidence indicates that body weight and adiposity can be tightly physiologically regulated through the coordinated action of distributed neurons and brain circuits, which regulate feeding and energy expenditure in response to changes in circulating hormones [3] and nutrients [4]. Consumption of a high-fat diet (HFD) has been shown to lead to lipid accumulation and inflammatory signaling in key neuronal subsets involved in the regulation of energy homeostasis [9,10,11,12], resulting in behavioral and biochemical resistance to insulin, leptin and other regulatory hormones and nutrient signals in the CNS. In order to understand the effects of dietary fat on obesity predisposition, we sought to identify molecular metabolic regulators that may be lipid sensitive. PPARc regulates adipogenesis and is the target of the thiazolidinedione (TZD) class of insulin sensitizing drugs [18], while PPARa regulates genes involved in hepatic fatty acid oxidation (FAO) [19] and lipoprotein metabolism [20] and is the molecular target of the fibrate class of dyslipidemia drugs [21]. PPARs have potent anti-inflammatory effects through transcriptional regulation of pro-inflammatory gene expression, both in the periphery [26] and central nervous system (CNS) [27]
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