Vegas-de Paramo. P¹, Vincenti-Pérez. A¹, Rivera. N¹, Vélez-Torres. W¹

Universidad Central del Caribe School of Medicine

INTRODUCTION: 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) binds to the melanocortin-4 receptor and generates a satiety signal in the hypothalamus neurons. CLGI inhibits JAK-2/STAT-3 signaling, downregulation of POMC expression, and the ability to regulate food intake. Activation of the α7 acetylcholine receptor (α7R) reduces pro-inflammatory cytokines indirectly through activation of the JAK2/STAT-3 pathway. We aim to uncover the molecular mechanisms behind α7R control of food intake and body weight.

METHODS: 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.

RESULTS: We observe that the α7KO mice on a HFD had higher body weight and plasma leptin and insulin levels than control and WT mice on a HDF. 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. 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. The phosphorylated leptin receptor expression was lower in the α7KO fed a HFD than in WT mice on a HFD.

CONCLUSION: 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.

IACUC APPROVAL NUMBER: 021-2022-37-01-PHA

Acknowledgments: NIGMS-RISE-R25GM110513, U54GM133807