Mechanistic drivers of thermogenic adipose tissue dysfunction in aging and obesity
Year: 2026
Type: article
Abstract: Population aging is accelerating worldwide and is accompanied by a growing burden of chronic metabolic diseases. Adipose tissue dysfunction represents a central mechanism linking aging and obesity to metabolic decline, contributing to chronic low-grade inflammation, impaired adipokine signaling, ectopic lipid deposition, and the whitening of thermogenic fat depots. Brown adipose tissue (BAT) plays a key role in adaptive thermogenesis through uncoupling protein 1 (UCP-1)-mediated mitochondrial uncoupling; however, its activity progressively declines with advancing age and excess adiposity. This narrative review synthesizes emerging biomolecular mechanisms that underlie impaired thermogenic function in the context of aging and obesity. We integrate evidence across three major regulatory domains: 1) intracellular thermogenic signaling, highlighting salt-inducible kinases (SIK2/3), as transcriptional repressors that limit UCP-1 expression when β3-adrenergic/protein kinase A (PKA) signaling is impaired; 2) autophagy-dependent secretion of acyl-CoA-binding protein (ACBP), which suppresses lipolysis, β-oxidation, and thermogenic signaling and may contribute to BAT whitening; and 3) immune-mediated regulation of thermogenic adipose tissue, with macrophage-modulating sympathetic signaling, inflammatory tone, and extracellular matrix remodeling through pathways involving NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome -monoamine oxidase A (MAOA), slit guidance ligand 3 (SLIT3)/ETS1, prolidase (PEPD), and immunoglobulin G (IgG). Collectively, these convergent mechanisms illustrate how aging and obesity impose coordinated constraints on brown and beige adipose tissue activation. By framing thermogenic decline as a regulated process, this review provides a conceptual basis for future studies aimed at preserving metabolic flexibility and promoting healthier aging.
Institution: Universidade de São Paulo
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: Taurine supplementation associated or not with multicomponent training: effect on white adipose tissue browning and metabolic and molecular responses using the metabolomics approach in elderly women with Sarcopenic Obesity, G2418999071, G3741427413, Nr1d1 function on the aging-associated Sarcopenia, G5687979891, G6345949040, G911243822
OpenAlex ID: W7203616649