The role of neuronal peroxisome proliferator-activated receptor delta in diet-induced obesity and hypothalamic inflammation
Kocalis, Heidi Elizabeth
Diet-induced obesity (DIO) is associated with low-grade hypothalamic inflammation, which contributes to insulin and leptin resistance leading to impaired energy balance regulation and obesity. Diets rich in monounsaturated fat reduce inflammation, improve insulin sensitivity and are less obesogenic than those high in saturated fat. The nuclear receptor Peroxisome proliferator-activated receptor delta (PPARδ) regulates the expression of genes involved in metabolism and inflammation in response to unsaturated fatty acids. This work tested the hypothesis that PPARδ functions as a fatty acid “sensor” which mediates the protective effects of dietary monounsaturated fats on DIO associated inflammation and insulin resistance in hypothalamic neurons. We began our investigation by feeding rats eucaloric high-fat diets enriched in saturated or monounsaturated fat. A clonal hypothalamic neuronal cell line was also treated with combinations of the saturated fatty acid palmitate or monounsaturated fatty acid oleate and with the PPARδ agonist GW0742 or antagonist GSK0660. Dietary or exogenous exposure to palmitate increased mRNA expression of the inflammatory cytokine interleukin-6 (IL-6). Activation of PPARδ in vivo by feeding rats an oleate-enriched diet or in vitro by oleate or GW0742 reduced expression of IL-6. These anti-inflammatory effects were reversed in neuronal cells exposed to physiologically relevant concentrations of palmitate and oleate in the presence of GSK0660, which also reduced insulin activation of Akt. Cre-LoxP technology was used to investigate the role of neuronal PPARδ in energy balance and DIO. On a chow diet, knockout (KO) mice have increased fat mass, despite reduced body weight and lean mass. Elevated hypothalamic inflammation was accompanied by leptin resistance and abnormal feeding and neuroendocrine responses to fasting. KO mice gained significantly more fat mass on a high-fat diet, but were resistant to diet-induced elevations in CNS inflammation and lipid accumulation. Gene expression analysis indicated increased expression of genes involved in fatty acid oxidation and increased expression/compensation by other PPARs. Collectively, this work has identified PPARδ as a protective fatty acid sensor, and revealed a role for neuronal PPARδ in the regulation of body composition, hypothalamic gene expression and feeding responses.