PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding

Abstract

Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.

DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons

“…3A–B). Because increased ROS levels were shown to increase POMC neuronal activation (Diano et al, 2011; Long et al, 2014), we then assessed c-fos immunolabeling in POMC neurons after a glucose load. Compared to controls, Drp1 fl/fl -POMC-cre:ER T2 mice showed an increase in c-fos immunoreactivity in POMC neurons 1 hour after the glucose load (Fig.…”

“…3L). Since we have previously shown (Diano et al, 2011; Long et al, 2014) that the activation and mRNA levels of the nuclear receptor Peroxisome proliferator-activated receptor gamma (PPARγ) are associated with POMC ROS levels and neuronal activation, next, we assessed whether PPARγ was altered in our animal model. Compared to control mice, Drp1 fl/fl -POMC-cre:ER T2 mice showed a significant increase of PPARγ protein levels in punches of the hypothalamic arcuate nucleus (Fig.…”

“…The molecular mechanisms by which hypothalamic neurons are able to sense these circulating signals and to respond by altering their activity levels have been the subject of many investigations. Studies from our laboratory have shown that reactive oxygen species (ROS), a by-product of nutrient oxidation, are important regulators of the anorexigenic and glucose-sensing pro-opiomelanocortin (POMC) neuronal activity (Andrews et al, 2008; Diano et al, 2011; Long et al, 2014). A positive correlation between POMC activity and ROS levels exists that leads to cessation of feeding and increased energy expenditure.…”

UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness

“…Glucose tolerance tests were performed in 16h fasted animals as previously reported (Kim et al, 2014; Long et al, 2014). Each animal received an ip injection of 2g/kg BW glucose (DeltaSelect, Germany) in sterile saline.…”

“…The hyperinsulinemic-euglycemic clamp protocol was measured as described previously (Ayala et al, 2006; Kim et al, 2014; Long et al, 2014; Toda et al, 2013), initiated in conscious and unrestrained mice after the fasting for four hours. The 90-min basal period ( t = –90 to 0 min) was followed by a 115-min clamp period ( t = 0 to 115 min) (Figure 3F).…”