Thyroid hormone as an endocrine switch between adipogenic and fibro-inflammatory cell remodeling in adipose tissue with implications for metabolic health

• Applicant: Dr. Kerstin Krause
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417784217

Thyroid hormones (TH) regulate adipocyte functions throughout various stages of development. The expansion and dysfunction of white adipose tissue (WAT) during obesity are central to the onset of metabolic complications, primarily through alterations in cellular composition, especially the increased presence of pro-inflammatory cells. Our own research supports this by demonstrating that TH deficiency is associated with a higher abundance of Zfp423GFP+ APCs in both visceral and inguinal fat depots, along with a notable increase in adipocyte size. Low TH levels induce Zfp423 expression, promoting differentiation into a lipid-storing white adipocyte phenotype, whereas high TH levels drive the formation and activation of a beige, energy-consuming phenotype. These findings suggest that TH plays an adaptive role in maintaining adipose tissue function by regulating Zfp423 expression, thereby influencing depot-specific APC commitment, adipocyte growth, and overall tissue function. In this context, the TH/TR/ZFP423 circuit may serve as a mechanistic and temporal link between fluctuations in TH levels, sympathetic tone, and nutritional status. It remains an open question whether and how TH influences the cellular composition and phenotypes within white AT under contemporary lifestyle conditions. Furthermore, if such an influence exists, it will be of interest to determine to what extent TH levels shape the trajectory of obesity-induced changes in AT. Accordingly, it is tempting to speculate that perivascular PDGFRβ-expressing cells act as a niche that translate fluctuations in peripheral TH levels into activation of either adipogenic or fibro-inflammatory pathways driving adipose fibrosis. Notably, recent results from phase 3 clinical trials using the TRβ-agonist resmetirom successfully demonstrated the mitigation of liver fibrosis in patients with non-alcoholic steatohepatitis. By elucidating how TH influence the balance between APCs and FIPs in AT, this project will provide important insights into the mechanisms linking TH levels, AT function, and metabolic health. These findings could open new avenues for novel treatment strategies to mitigate obesity-associated metabolic complications and improve overall systemic health.

• DFG Programme: Research Grants