Epigenetics‐Driven Appetite System Disorders and PI3K/AKT Signaling Activation Mediate a Weight Gain Resistance Phenotype Induced by a High‐Fat Diet in Male Rats

ABSTRACT Objective Some patients with anorexia nervosa (AN) exhibit an aversion to high‐fat food. The hypothalamus plays a crucial role in feeding behavior. This study investigated the role of epigenetic modifications in the hypothalamus of male rats exhibiting a weight gain resistance (WR) phenotype induced by a high‐fat diet (HFD). Method Male Sprague–Dawley (SD) rats were divided into normal diet (ND) and HFD groups for 9 weeks. Rats in the HFD group were then divided into HFD‐induced obese (HFO) or HFD‐induced WR phenotype (HFWR) groups, and body weight and food intake were monitored for 24 days. Samples such as hypothalamus and serum were collected. Results The hypothalamus of HFWR rats showed increased 5‐methylcytosine (5mC) levels. Whole‐genome bisulfite sequencing (WGBS) analysis revealed that the level of 5mC in the hypothalamic DNA of HFWR rats was higher than that of HFO rats. The hypothalamus of HFWR rats displayed molecular disturbances in appetite systems. Through integrated analysis of the methylome and transcriptome, we discovered that alterations in methylation levels directly influenced changes in the galanin and IGF systems. Five genes ( Aurkb , Cdkn1a , Galr1 , ND2 , and Tf ) with promoter hypermethylation may be involved in appetite system disturbances. Furthermore, HFD‐induced alteration of 5mC affects PI3K/Akt signaling activation, resulting in increased neuroinflammation and apoptosis in the ventromedial nucleus of the hypothalamus (VMH) in HFWR rats. Discussion Our study suggests that 5mC‐mediated molecular disturbances in the hypothalamic appetite system and activation of PI3K/Akt signaling in the VMH may serve as a potential pathogenic basis for HFWR.