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Publication
Effects of FGF21, soluble TGFBR2, and environmental temperature on metabolic
dysfunction in lipodystrophic mice.
Authors Maung JN, Chen Y, Hoose KS, Adler RE, Hariri H, Dickson MJ, Hetrick TA, Ferguson
GA, Schill RL, Mori H, Uranga RM, Lewis KT, Hermsmeyer ID, Gilio D, de Solis C,
Toliver A, Davidsohn N, Oral EA, MacDougald OA
Submitted By Submitted Externally on 12/12/2025
Status Published
Journal JCI insight
Year 2025
Date Published 8/22/2025
Volume : Pages 10 : Not Specified
PubMed Reference 40663389
Abstract Metabolic health is influenced by adipose tissue, and obesity and lipodystrophy
are characterized by inflammation and metabolic dysfunction. Whereas obesity and
lipodystrophy treatments involve pharmacological approaches and lifestyle
changes, these therapies require long-term, repeated dosing and are not
successful for all patients. Gene therapy with targets such as FGF21 and soluble
TGF-ß receptor 2 (sTGFBR2) provides an alternative approach, specifically in
lipodystrophy. Preclinical experiments in mice housed at 22°C are confounded by
a mild cold stress not generally experienced by humans, which can negatively
affect translation of metabolic therapeutics. In this study, we investigated
effects of FGF21/sTGFBR2 combination gene therapy on obese and lipodystrophic
mice and how housing temperature influences therapeutic efficacy. In obese mice,
FGF21/sTGFBR2 improved insulin resistance and hyperlipidemia more dramatically
at warmer temperatures. In lipodystrophic mice on a high-fat diet, combination
therapy required adipose tissue to improve insulin resistance at 30°C, whereas
FGF21 alone improved insulin resistance at 22°C. Transcriptomic analyses
revealed that lipodystrophic mice had upregulated hepatic cell proliferation and
fibrosis pathways and that FGF21 promoted hepatic metabolism. Thus, metabolic
dysfunction caused by lipodystrophy is improved by targeting FGF21 and TGFB
signaling, but effectiveness in preclinical models may be dependent upon
environmental temperature and presence of adipose tissue.




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