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Hedi Raizer

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What is UCP1?

UCP1 is the mitochondrial uncoupling protein that defines brown and beige adipocytes. This page covers its identity, the pathways that regulate it, and the preclinical models used to study it.

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What is UCP1?

Uncoupling protein 1 (UCP1), also known as thermogenin, is a member of the mitochondrial anion carrier protein family. It is the defining molecular marker of brown adipose tissue (BAT) and of beige adipocytes that arise in white adipose tissue (WAT) depots. UCP1 is an inner mitochondrial membrane protein that dissipates the proton gradient generated by the electron transport chain, uncoupling oxidative phosphorylation from ATP synthesis and releasing energy as heat. The human UCP1 gene encodes a 307-amino-acid protein with a calculated molecular weight of approximately 33 kDa. No sequence, formula, or identifier beyond these is provided in the evidence block.

The work described on this page centres on the transforming growth factor-beta (TGF-β) superfamily and its downstream SMAD signalling, which has been shown to regulate adipose tissue browning and UCP1 expression in preclinical models.

Research Studies

Follistatin and adipose browning in atherosclerosis-prone mice

Follistatin (FST) binds to and neutralizes members of the TGF-β superfamily, regulating skeletal muscle, adipose, and bone homeostasis. In mice, FST promotes adipose browning and enhances energy metabolism, leading to improved plasma lipid profiles [1]. Because brown adipose tissue activation has been associated with reduced atherosclerosis, one study investigated the anti-atherogenic potential of FST. Transcriptomic and metabolomic analyses of the Hybrid Mouse Diversity Panel (HMDP) revealed that Fst expression was negatively correlated with aortic lesion area [1]. This finding was observed in mice and in HMDP-derived data; no human intervention data are reported in the evidence block.

GDF-11 and cold-induced browning in mice and 3T3-L1 cells

Growth differentiation factor 11 (GDF-11) is a circulating member of the TGF-β superfamily. In a study of adipose tissue plasticity, mice were exposed to cold to induce browning, and GDF-11 expression and SMAD2/3 activation were assessed in brown adipose tissue, visceral and subcutaneous white adipose tissue, and skeletal muscle [2]. The study combined in vivo results with in vitro approaches using 3T3-L1 cells [2]. The evidence block does not provide the direction or magnitude of the effect, only that the study investigated whether GDF-11 regulates WAT browning and the underlying mechanisms.

Finerenone and adipose browning in the context of atrial fibrillation

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist with anti-inflammatory, antifibrotic, and metabolic effects. In prior large trials, finerenone was associated with a lower incidence of atrial fibrillation, and preclinical studies suggest it promotes browning of adipose tissue and improves epicardial adipose tissue characteristics [3]. A single-centre, randomized, investigator-blinded pilot trial (NCT07799519) is planned to enrol 40 patients after catheter ablation with pulmonary vein isolation to assess whether finerenone reduces atrial fibrillation recurrence [3]. The browning-related observations cited in the rationale are preclinical; the trial itself is designed to assess arrhythmia recurrence, not UCP1 directly.

Exercise and diet effects on adipose tissue and muscle in metabolic syndrome

A clinical study (NCT01793896) is examining whether physical exercise and/or a Mediterranean diet preserve adipose tissue functionality and retard skeletal muscle aging in middle-aged volunteers with metabolic syndrome [4]. The study assesses mitochondrial biogenesis and accumulation of reactive oxygen species, and proposes that these interventions activate pathways homologous to caloric restriction [4]. The evidence block does not specify UCP1 as an endpoint; the relevance to UCP1 is indirect, through adipose tissue functionality.

Syringaresinol and the skeletal muscle SIRT1–FNDC5/irisin axis

Syringaresinol (SYR), a plant-derived lignan, was examined for its effects on skeletal muscle SIRT1-related FNDC5/irisin signalling and high-fat-diet-associated metabolic outcomes. In differentiated C2C12 myotubes, SYR was tested alongside the SIRT1 activator SRT1720 and the SIRT1 inhibitor EX-527 to assess irisin regulation [5]. This work is in vitro and in a mouse myoblast cell line; it does not directly address UCP1.

Time-restricted feeding and HIIT effects on thermogenesis-related proteins in diabetic rats

A study in male Wistar rats evaluated the independent and combined effects of time-restricted feeding (TRF) and high-intensity interval training (HIIT) on thermogenesis-related protein abundance in white adipose tissue of diabetic rats [6]. Forty rats were divided into normal and diabetic groups. The evidence block does not list UCP1 among the proteins measured, only that thermogenesis-related protein abundance was assessed. This is an animal model of diabetes.

β2-adrenergic receptor stimulation and human beige adipocyte differentiation

β-adrenergic receptors drive the induction of beige adipocytes in rodents and humans, but the dominant human subtype, β2-AR or β3-AR, remains debated. One study aimed to confirm whether human adipose-derived mesenchymal stem cell (hADSC)-derived adipocytes can serve as a beiging-competent model under human-relevant conditions [7]. This work is in human cells in vitro; it does not report UCP1 protein or function directly in the evidence block.

Bombesin receptor-activated protein homolog deficiency and metabolic dysfunction in mice

Bombesin receptor-activated protein (BRAP) and its mouse homolog, BC004004, are expressed in the central nervous system. In feeding experiments, BRAP homolog knockout mice (BC004004-/-) showed reduced preference for a high-fat diet and alleviated metabolic dysfunction when treated with a high-fat diet [8]. This is a mouse genetic model; the evidence block does not link this directly to UCP1.

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