Biol Sex Differ. 2025 Dec 31. doi: 10.1186/s13293-025-00787-4. Online ahead of print.
ABSTRACT
This review takes a close look at the biology of brown and beige fat, not just as thermogenic tissues, but as active metabolic organs influenced by sex, hormones, age, and even environment. Brown adipose tissue (BAT) and beige adipocytes differ in their origins, gene expression, and regulation. These differences are especially relevant when considering how they behave in males and females. Across both animal and human studies, females show higher BAT volume and more efficient thermogenic activity. Estrogen, acting mainly through estrogen receptor alpha (ERα), increases uncoupling protein 1(UCP1) expression, promotes mitochondrial biogenesis, and supports the formation of beige fat within white adipose tissue. In contrast, testosterone and glucocorticoids tend to reduce thermogenic gene expression and shift fat storage toward visceral depots, which increases metabolic risk, particularly in men. These hormone-driven effects are not limited to adulthood. Puberty, pregnancy, menopause, and andropause all influence thermogenic capacity in sex-specific ways. We also outline the key signaling pathways behind beiging such as PR domain-containing 16 (PRDM16), Peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), and β3-adrenergic signaling and how they interact with sex hormones to shape thermogenic responses. Findings from Positron Emission Tomography with Computed Tomography (PET/CT) imaging, genetic models, and molecular profiling show that beige and brown fat are regulated by distinct mechanisms and developmental cues depending on sex. We also review how BAT activity is linked to a lower risk of type 2 diabetes, cardiovascular disease, and inflammation, particularly in women with obesity. Conditions like Polycystic Ovary Syndrome (PCOS), hormone therapy, and exposure to endocrine-disrupting chemicals further influence BAT function in sex dependent ways. Understanding how brown and beige fat respond differently in men and women to internal and external signals, is critical. These differences have clear implications for developing targeted, more effective strategies to treat obesity and metabolic disease.
PMID:41476314 | DOI:10.1186/s13293-025-00787-4