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. cocaine-and amphetamine-regulated transcript This research was funded by a statutory grant AWF/NF/ZB1/2025 from Academy of Physical Education in Katowice and BNW-1-148/K/4/O from the Medical University of Silesia, Katowice, additionally, by the National Science Centre, Poland grants no. 2024/53/N/NZ7/03956. Laboratory of Molecular Biology, Institute of Physiotherapy and Health Sciences, Academy of Physical Education, Katowice, Poland Mateusz Grabowski, Konstancja Grabowska, Marta Nowacka-Chmielewska & Andrzej Małecki Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland Institute of Diabetes and Obesity, Helmholtz Center Munich, Munich, Germany Collegium Medicum, Faculty of Medicine, WSB University, Dabrowa Górnicza, Poland The authors declare no competing interests.
Animals were treated using the protocols approved and monitored by the Local Committee for the Care and Use of Laboratory Animals in Katowice, Poland (permission no. 3/21, 15th February 2021), and all experiments were performed following relevant guidelines and regulations. Manuscripts presenting studies that have been reported in accordance with the ARRIVE guidelines Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Below is the link to the electronic supplementary material.
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