Glucocorticoid Effects on Adipose Tissue Metabolism

Glucocorticoids are steroid hormones that modulate energy homeostasis by acting on adipose tissue, a central organ for lipid storage and endocrine signalling. Through binding to the glucocorticoid receptor (GR), these hormones regulate gene networks involved in lipogenesis, lipolysis and adipocyte differentiation. Acute exposure enhances lipolysis via activation of hormone-sensitive lipase, whereas chronic elevation promotes visceral fat accumulation by upregulating adipogenic programmes and repressing key inhibitors of adipocyte maturation. Local regeneration of active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 further amplifies these effects in adipocytes and stromal cells. Crosstalk with immune cells, notably macrophages, integrates metabolic and inflammatory responses, and microRNA-mediated fine-tuning of cortisol metabolism adds another layer of regulation. The net result of sustained glucocorticoid excess is central obesity, insulin resistance and increased cardiometabolic risk, a scenario commonly observed in Cushing’s syndrome and during long-term therapeutic use of synthetic analogues.

Research from Nature Portfolio

Recent studies have shown that glucocorticoids trigger expression of the transcription factor Krüppel-like factor 9 (KLF9) in adipose-resident macrophages, leading to their deactivation and reduced secretion of inflammatory mediators. Elevated KLF9 recruits a SIN3A-HDAC complex to promoters of cytokine genes, dampening STAT3 signalling in neighbouring adipocytes. This dampening decreases thermogenic gene expression, while simultaneously promoting lipid accumulation. Genetic deletion of KLF9 in myeloid cells protects mice from glucocorticoid-induced obesity, highlighting KLF9 as a pivotal node linking anti-inflammatory and adverse metabolic actions of glucocorticoids.

Glucocorticoid Effects on Adipose Tissue Metabolism publication trend

The graph below shows the total number of articles in glucocorticoid effects on adipose tissue metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

Glucocorticoids: Steroid hormones regulating carbohydrate, lipid and protein metabolism via the glucocorticoid receptor.

Adipocytes: Fat cells specialised in storing energy as lipids and secreting adipokines.

Macrophages: Innate immune cells within adipose tissue that influence metabolic and inflammatory processes.

Lipogenesis: Biochemical pathway for the synthesis of fatty acids and triglycerides in adipocytes.

Lipolysis: Enzymatic hydrolysis of stored triglycerides into free fatty acids and glycerol.

Adipogenesis: Differentiation of precursor cells into mature adipocytes capable of lipid storage.

microRNA: Small non-coding RNA molecules that post-transcriptionally regulate gene expression.

Krüppel-like factor 9 (KLF9): A transcription factor induced by glucocorticoids in macrophages that modulates inflammatory and metabolic gene networks.

References

1. Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes.. Journal of Lipid Research (1994).
2. Genome-Wide Analysis of Glucocorticoid Receptor Binding Regions in Adipocytes Reveal Gene Network Involved in Triglyceride Homeostasis. PLOS ONE (2010).
3. The Role of microRNA in the Regulation of Cortisol Metabolism in the Adipose Tissue in the Course of Obesity. International Journal of Molecular Sciences (2024).
4. High-fat diet-induced increase in glucocorticoids contributes to adipogenesis in obese mice. Biomedical Journal (2024).
5. Loss of epidermal glucocorticoid receptor protects against whole body metabolic dysfunction upon chronic corticosterone treatment. Molecular Metabolism (2023).
6. Glucocorticoids increase adiposity by stimulating Krüppel-like factor 9 expression in macrophages. Nature Communications (2024).