Weight regain, its immunological impact

Abstract

Obesity is a chronic non-communicable disease characterized by a persistent inflammatory immunometabolic phenotype. With each cycle of weight regain, the inflammatory response is amplified through mechanisms of immunological and epigenetic memory.

Adipose tissue expansion and dysfunction promote hypoxia, endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and the release of pro-inflammatory cytokines, accompanied by infiltration and reprogramming of immune cells, particularly macrophages and T lymphocytes.

Weight loss improves insulin sensitivity and reduces multiple inflammatory markers; however, these clinical and metabolic improvements do not imply complete resolution of the immunological and epigenetic alterations induced by obesity. Immunological and epigenetic memory persists within adipose tissue and is capable of modifying its response upon renewed exposure to excess energy.

Caslin and colleagues demonstrated in a murine model that repeated cycles of weight regain induce a phenomenon of trained immunity in adipose tissue macrophages. Following weight loss, these cells retain functional reprogramming that, upon weight regain, triggers an amplified inflammatory response, characterized by increased TNF-α production and impaired glucose homeostasis. Subsequent studies extended this concept to adaptive immunity, demonstrating the persistence of memory T lymphocytes associated with an adverse metabolic response during recurrent cycles of weight regain.

Hinte and colleagues demonstrated, through transcriptomic and epigenomic analyses, that even after substantial weight loss, adipocytes retain obesity-induced epigenetic modifications. This persistent memory shapes subsequent transcriptional responses and promotes accelerated weight regain following renewed exposure to a high-fat, hypercaloric diet.

Recent evidence suggests that weight regain may reprogram immune progenitor cells, sustain chronic inflammation, and promote the progression of atherosclerosis. Collectively, these findings support the hypothesis that weight regain constitutes a biologically distinct process from the initial development of obesity, characterized by the reactivation of persistent immunological and epigenetic memory.

Maintaining weight loss not only preserves the metabolic benefits achieved but may also represent a strategy to prevent the reactivation of immunological and epigenetic mechanisms associated with the progression of cardiometabolic complications.