Hormonal Adaptations and the Challenge of Sustained Weight Loss among Patients with Obesity or Overweight

Dr Nitin Kapoor, Professor and Head (Unit 1), Dept. of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore (TN) India.

Weight loss triggers hormonal adaptations, like increased ghrelin, that may drive appetite and promote weight regain despite diet or exercise interventions.

Weight loss remains a cornerstone in managing obesity, yet long-term success is often undermined by physiological adaptations that favor weight regain. The recent meta-analysis by Jin et al. (2025) provides comprehensive insights into how appetite-related gut hormones—ghrelin, peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and cholecystokinin (CCK)—respond to weight loss induced by calorie restriction, exercise, or their combination.

The analysis of 127 studies reveals a consistent increase in total ghrelin post-weight loss, highlighting its role in stimulating appetite and potentially driving compensatory eating behaviors. Conversely, changes in anorexigenic hormones such as PYY and active GLP-1 were less consistent, with decreases observed predominantly in non-randomized studies. Notably, the magnitude of weight loss correlated with greater elevations in ghrelin, emphasizing the dose-dependent nature of these hormonal adaptations. These findings underscore that weight loss is not merely a behavioral or dietary challenge but is intricately counteracted by endocrine mechanisms.

Understanding these hormonal shifts could inform personalized strategies that combine dietary, exercise, and potentially pharmacologic interventions to mitigate compensatory appetite responses. Future research should aim to clarify sex-specific differences and the role of body composition in modulating gut hormone responses to improve long-term weight maintenance.

(Source: Jin Z, Li J, Thackray AE, Shen T, Deighton K, King JA, Stensel DJ. Fasting appetite-related gut hormone responses after weight loss induced by calorie restriction, exercise, or both in people with overweight or obesity: a meta‐analysis: Physiology and Biochemistry. International Journal of Obesity. 2025 May;49(5):776-92. )