# Hormones, heat, and health: a comprehensive review of sex-based differences in brown and beige fat biology

## TL;DR

This review explores how brown and beige fat function differently in males and females, highlighting the role of hormones and sex-specific differences in thermogenesis and metabolic health.

## Contribution

The paper provides a comprehensive analysis of sex-based differences in brown and beige fat biology, emphasizing hormonal regulation and implications for metabolic disease.

## Key findings

- Females consistently show higher BAT volume and thermogenic activity compared to males, influenced by estrogen.
- Beige adipocytes originate from diverse progenitor cells and show sex-dependent activation in response to environmental and hormonal cues.
- Endocrine disruptors like BPA and phthalates impair beiging and promote BAT whitening with sex-specific effects.

## 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.

Females consistently show higher UCP1 expression and BAT activity than males across species, influenced by estrogen dependent mitochondrial and sympathetic regulation.Hormonal regulation of BAT and beige adipocytes is profoundly sex specific, with estrogen and thyroid hormones enhancing thermogenesis in females; progesterone exerting dose and context dependent effects; androgens and glucocorticoids generally suppressing thermogenic activity, particularly in males.Beige adipocytes arise from diverse progenitor populations, including smooth muscle like and PDGFRα + cells, with their activation influenced by environmental and hormonal cues that show sex-dependent variation in beiging efficiency.Cold exposure triggers more robust browning responses in females, including greater UCP1 induction, denser sympathetic innervation, and higher beige adipocyte recruitment.Environmental endocrine disruptors such as BPA and phthalates impair beiging and promote BAT whitening, with potential sex specific susceptibility due to differential estrogen receptor signaling.

Females consistently show higher UCP1 expression and BAT activity than males across species, influenced by estrogen dependent mitochondrial and sympathetic regulation.

Hormonal regulation of BAT and beige adipocytes is profoundly sex specific, with estrogen and thyroid hormones enhancing thermogenesis in females; progesterone exerting dose and context dependent effects; androgens and glucocorticoids generally suppressing thermogenic activity, particularly in males.

Beige adipocytes arise from diverse progenitor populations, including smooth muscle like and PDGFRα + cells, with their activation influenced by environmental and hormonal cues that show sex-dependent variation in beiging efficiency.

Cold exposure triggers more robust browning responses in females, including greater UCP1 induction, denser sympathetic innervation, and higher beige adipocyte recruitment.

Environmental endocrine disruptors such as BPA and phthalates impair beiging and promote BAT whitening, with potential sex specific susceptibility due to differential estrogen receptor signaling.