The impact of obesity on appetite regulation during nutritional ketosis

Abstract Obesity is a major global health concern, and sustained weight loss is often limited by increased appetite. The ketogenic diet (KD) has emerged as a potential appetite-modulating strategy. However, its neural and hormonal mechanisms remain incompletely understood. In this study, diet-induced obesity (DIO) was introduced to mice by 6-week Western chow feeding, followed by a 14-day KD intervention. Age-matched lean controls were maintained. We assessed consummatory behavior, biochemical and molecular markers of appetite regulation in the hypothalamus. Western chow feeding induced a metabolic phenotype characterized by hyperglycemia, hyperinsulinemia, hyperleptinemia, elevated HOMA-IR, reduced ghrelin and GLP-1, and decreased hypothalamic Mc4r expression. KD improved glucose and lipid profiles and reduced snack-directed behavior in lean and obese mice. Although food intake declined, caloric intake remained comparable due to the higher energy density of ketogenic chow. KD increased circulating β-hydroxybutyrate levels, particularly in lean mice. Hypothalamic Ghsr expression decreased, whereas Cart and Mc3r were upregulated irrespective of phenotype, indicating remodeling of melanocortin signaling. Selective Agrp upregulation in lean mice did not promote hyperphagia, suggesting compensatory adaptation. Overall, KD suppresses consummatory behavior and improves metabolic parameters. However, obesity-associated neuroendocrine alterations persist despite weight reduction.