Abstract 1395 The anti-inflammatory role of the alpha 7 receptors in diet-induced obesity

Obesity is a significant public health concern due to its association with chronic diseases such as diabetes, heart disease, and certain types of cancer. Obesity can contribute to chronic low-grade inflammation (CLGI), which is linked to leptin resistance. Leptin regulates food intake by binding its receptor, activating the JAK-2/STAT-3 signaling and proopiomelanocortin (POMC) transcription. One of the POMC products (α-MSH) activates the melanocortin-4 receptor (Mc4R) and inhibits the Kir 7.1 K+ channels to generate a satiety signal in the hypothalamus neurons. CLGI inhibits JAK-2/STAT-3 signaling and downregulates POMC expression, which results in increased food intake. Activation of the α7 acetylcholine receptor (α7R) reduces pro-inflammatory cytokines indirectly through activation of the JAK2/STAT-3 pathway; also, activation of α7R reduces body weight and food intake in mice fed a HFD. We aim to uncover the molecular mechanisms behind α7R control of food intake and body weight. Male WT and α7 knockout mice (α7KO) mice received a high-fat diet (HFD) or a control low-fat diet (LFD) for 16 weeks. Blood and hypothalamus were collected for protein analysis. Our data showed that α7KO mice on a HFD had higher body weight and plasma leptin than control and WT mice on a HFD. As expected, the α7KO mice fed a HFD had higher plasma TNF-α and IL-6 cytokine levels than control and WT mice on a HFD. Hypothalamus western blot analyses showed reduced α-7R protein expression in WT mice on a HFD. The phosphorylated leptin receptor expression was lower in the α7KO fed a HFD than in WT mice on a HFD. Phosphorylated STAT-3 protein levels were lowered in the α7KO compared to WT mice, regardless of diet. POMC protein expression decreased in the α7KO mice on a HFD compared to the control. Our data suggests that in diet-induced obesity, the α7R decreases IL-6 levels, activating the leptin receptor and increasing POMC expression to reduce body weight. We plan to investigate the role of the α7R in Mc4R and kir 7.1 function to control the satiety signal. Acknowledgments: NIGMS-RISE-R25GM110513 U54GM133807.