Thermogenic adipose tissue in older adults with obesity: a narrative review of mechanisms, brown fat resistance, and the translational relevance of exercise and nutrition

FIGURE 1. Classic and non-classic thermogenic mechanisms in thermogenic adipose tissue. (A) In classic UCP1-dependent thermogenesis, cold exposure activates the hypothalamic thermoregulatory center and sympathetic nervous system, leading to norepinephrine release and β3-adrenergic receptor activation in brown adipocytes. This stimulates adenylyl cyclase, promotes cAMP generation from ATP, activates the cAMP/PKA pathway, and induces hormone-sensitive lipase-mediated lipolysis. Released fatty acids serve as mitochondrial oxidative substrates and activate UCP1-dependent proton leak, thereby dissipating the proton gradient as heat. (B) The creatine cycle represents a UCP1-independent ATP-consuming futile cycle. Creatine kinase B (CKB) mediates creatine phosphorylation, whereas tissue-non-specific alkaline phosphatase (TNAP) promotes phosphocreatine dephosphorylation, resulting in continuous ATP turnover and heat generation. (C) Lipolysis and re-esterification form another futile cycle in which fatty acids released from lipid droplets are re-esterified back into triglycerides, consuming ATP and contributing to energy dissipation as heat. (D) The PM20D1-N-acyl amino acid pathway generates…

FIGURE 2. Conceptual framework of age-related brown fat resistance in obese older adults. This figure presents age-related brown fat resistance as a multidimensional tissue-level phenotype in obese older adults, relative to metabolically matched younger individuals. The central construct is characterized by a higher threshold for thermogenic recruitment, weaker responses to physiological stimuli, and reduced durability of induced beige phenotypes after stimulus withdrawal. The left side summarizes converging biological inputs, including weakened sympathetic drive and β-adrenergic signaling, chronic low-grade inflammation, endocrine remodeling, sarcopenia with impaired muscle-to-adipose communication, and adipose remodeling with fibrosis and reduced perfusion. The lower panel lists operational readouts, including reduced BAT or beige recruitment, lower UCP1 and thermogenic gene induction, blunted responses to cold, exercise, and nutrition, reduced substrate uptake and heat production, and poor maintenance of the beige phenotype. The right side distinguishes this construct from cold-induced thermogenesis failure, sympathetic dysregulation, and generalized metabolic inflexibility. The…

FIGURE 3. Exercise-exerkine-adipokine-batokine network in obese older adults. This Figure illustrates how exercise may influence thermogenic adipose tissue through inter-organ communication among skeletal muscle, liver, white adipose tissue, beige adipocytes, and brown adipose tissue. Skeletal muscle contraction can induce exercise-responsive mediators such as acute exercise-induced IL-6 and METRNL, while reducing adverse myostatin signaling. The liver and adipose tissues contribute additional circulating mediators, including FGF21, adiponectin, NRG4, and 12,13-diHOME. Together, these exerkines, adipokines, and batokines may support browning, UCP1-related thermogenic gene expression, catecholamine-linked remodeling, insulin sensitivity, and mitochondrial function. In obese older adults, sarcopenia, reduced muscle mass, altered batokine output, inflammaging, and BAT loss may weaken this endocrine network and contribute to impaired thermogenic responsiveness. Created in BioRender. Qiao, H. (2026) https://BioRender.com/hwhcbso.

FIGURE 4. Intracellular Mechanisms of nutrient-mediated thermogenic activation and browning in brown and beige adipocytes. This figure summarizes candidate thermogenic nutrients and dietary bioactive compounds according to their main pathway nodes and compares the strength of evidence between rodent and human studies. The left column summarizes typical rodent findings, in which caffeine or tea polyphenols, capsaicin, omega-3 fatty acids, polyphenols or spices, and selected vitamins or minerals have been associated with changes in UCP1 expression, browning markers, energy expenditure, or mitochondrial support. The central panel illustrates putative nutrient-linked signaling pathways, including sympathetic and β-adrenergic signaling, TRPV1/TRPA1 activation, GPR120 or lipid-mediated signaling, AMPK/SIRT1-related mitochondrial adaptation, and cofactor support for substrate uptake and oxidative metabolism. The right column highlights that human evidence is generally smaller, more heterogeneous, and often based on surrogate readouts such as PET uptake, cold-induced thermogenesis, energy expenditure, circulating biomarkers, or metabolic endpoints. In obese older adults, these nutrients should…

FIGURE 5. Integrated conceptual framework of exercise, nutrition, and thermogenic adipose tissue in obese older adults. This figure integrates exercise and nutrition as complementary strategies for improving the systemic and tissue-level conditions required for thermogenic adipose activation in obese older adults. Endurance and resistance exercise may preserve skeletal muscle mass and promote exercise-responsive signals, including irisin, acute exercise-induced IL-6, FGF21, METRNL, and reduced myostatin signaling. Thermogenic nutrition may provide additional pathway-specific inputs, including omega-3 PUFA-related GPR120 or lipid signaling, caffeine and tea catechin-related sympathetic activation, capsaicin and spice-related TRPV1/TRPA1 signaling, and polyphenol-related AMPK/SIRT1-mediated mitochondrial adaptation. These potential effects are constrained by sarcopenia, inflammaging, and β-adrenergic resistance, which may reduce exerkine production, impair mitochondrial function, and weaken sympathetic signaling to BAT. If these barriers are partially overcome, the expected net effects may include greater BAT and beige adipose activation, improved glucose and lipid clearance, better…