Estrogen Modulation of Metabolic Health in Adipose Tissue

Oestrogens exert pivotal influences on adipose tissue physiology, orchestrating lipid storage, energy expenditure and inflammatory tone to maintain metabolic homeostasis. In premenopausal individuals, circulating 17β-oestradiol and its binding to oestrogen receptors in adipocytes regulate lipogenesis and lipolysis via both genomic and non-genomic mechanisms. These actions promote subcutaneous fat deposition over visceral expansion, enhance insulin sensitivity and support mitochondrial function. Loss of oestrogen signalling, as seen during menopause or experimental ovariectomy, precipitates altered adipocyte differentiation, accumulation of visceral adipose depots and aberrant lipid handling, contributing to insulin resistance, dyslipidaemia and low-grade inflammation. Mechanistically, oestrogen receptor α modulates key pathways including AMP-activated protein kinase activation and suppression of ubiquitination pathways that affect insulin receptor signalling. Modulation of peroxisome proliferator-activated receptor gamma activity and cross-talk with inflammatory mediators further refines adipose tissue responses to nutrient excess. Therapeutic strategies targeting oestrogen receptors or their downstream effectors hold promise for ameliorating obesity-related complications and improving metabolic resilience across the lifespan.

Research from Nature Portfolio

Recent studies have elucidated ligand-independent roles of oestrogen receptor α (ERα) in systemic glucose and lipid homeostasis. One investigation demonstrates that a peptide derived from the ERα 1–280 domain stabilises IRS1 by inhibiting ubiquitination, thereby enhancing hepatic insulin sensitivity and restoring glucose tolerance in obese rodent models without requiring oestrogen binding. Administration of this peptide also led to improved serum lipid profiles and reduced adiposity. These findings reveal novel non-classical functions of ERα in regulating adipose crosstalk with hepatic and muscle tissues, opening potential avenues for peptide-based insulin-sensitising therapies.

Estrogen Modulation of Metabolic Health in Adipose Tissue publication trend

The graph below shows the total number of articles in estrogen modulation of metabolic health in adipose tissue across all publications each year (not limited to Nature Index journals).

Technical terms

Adipocyte: A fat cell specialised for the storage of triglycerides.

Oestrogen receptor α (ERα): A nuclear receptor mediating genomic and non-genomic actions of oestrogens in metabolic tissues.

Ovariectomy (OVX): A surgical procedure to remove ovaries, used as a model of oestrogen deficiency.

AMP-activated protein kinase (AMPK): A cellular energy sensor regulating lipid and glucose metabolism.

Lipogenesis: The metabolic pathway responsible for the synthesis of fatty acids and triglycerides.

References

1. An estrogen receptor α-derived peptide improves glucose homeostasis during obesity. Nature Communications (2024).
2. Butyrate mitigates metabolic dysfunctions via the ERα-AMPK pathway in muscle in OVX mice with diet-induced obesity. Cell Communication and Signaling (2023).
3. The Effect of Ovariectomy and Estradiol Substitution on the Metabolic Parameters and Transcriptomic Profile of Adipose Tissue in a Prediabetic Model. Antioxidants (2024).
4. Adipocyte Metabolism and Health after the Menopause: The Role of Exercise. Nutrients (2023).
5. Estrogen Regulation of Adiposity and Fuel Partitioning EVIDENCE OF GENOMIC AND NON-GENOMIC REGULATION OF LIPOGENIC AND OXIDATIVE PATHWAYS*. Journal of Biological Chemistry (2005).
6. Estrogen: An Emerging Regulator of Insulin Action and Mitochondrial Function. Journal of Diabetes Research (2015).
7. Estrogen Signaling in Metabolic Inflammation. Mediators of Inflammation (2014).