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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-\u03b2 receptor 2 (sTGFBR2) provides an alternative approach, specifically in lipodystrophy. Preclinical experiments in mice housed at 22\u00b0C 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\u00b0C, whereas FGF21 alone improved insulin resistance at 22\u00b0C. 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.<\/jats:p>","DOI":"10.1172\/jci.insight.194882","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T16:00:20Z","timestamp":1752595220000},"source":"Crossref","is-referenced-by-count":1,"title":["Effects of FGF21, soluble TGFBR2, and environmental temperature on metabolic dysfunction in lipodystrophic mice"],"prefix":"10.1172","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4289-0614","authenticated-orcid":true,"given":"Jessica N.","family":"Maung","sequence":"first","affiliation":[{"name":"Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, 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