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Adipose Tissue_Appetite_and Obesity

MON-675 - Lmna T10I and R482Q mice have reduced voluntary running, energy metabolism, and altered adipose gene expression in the absence of lipodystrophy

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor
Disclosure(s):
Elif A. Oral, MD: No relevant disclosure to display
Lipodystrophy syndromes are characterized by selective loss and dysfunction of adipose tissue, leading to insulin resistance, dyslipidemia, and hepatic steatosis. Pathogenic variants in LMNA, encoding lamin A/C, are the most common cause of monogenic lipodystrophy, yet the mechanisms linking LMNA dysfunction to adipose loss and metabolic disease remain incompletely understood. We generated Lmna knock-in mouse models of two human disease variants: R482Q, the most common cause of familial partial lipodystrophy type 2 (FPLD2), and T10I, associated with severe generalized lipodystrophy. Biallelic Lmna R482Q mice exhibited impaired postnatal growth, reduced mobility, and preweaning lethality, phenocopying global Lmna deficiency - subsequent studies were thus performed in monoallelic R482Q mice. Despite preserved body composition, adipose depot weights, and whole-body glucose homeostasis until ~80 weeks of age, adipose tissue from R482Q mice demonstrated reduced lipid metabolism and mitochondrial gene expression accompanied by increased inflammatory signaling, consistent with human FPLD2. In contrast, Lmna T10I mice, including biallelic animals, survived to adulthood and did not develop lipodystrophy: body composition, adipose depot weights, and glucose homeostasis were not altered to ~80 weeks of age. However, bulk RNA-sequencing of T10I adipose tissue revealed variant-specific transcriptional changes, including reduced lipid metabolism gene expression alongside increased mitochondrial pathways and reduced inflammatory signatures. Environmental and dietary stressors, including altered light cycles, housing temperatures, or high-fat/western/low-fat diets, were insufficient to induce lipoatrophy. However, a striking shared behavioral phenotype was a reduction in voluntary running activity in T10I and aged R482Q mice – although maximum speeds were similar, time spent running and distance traveled daily were reduced by >50%. Importantly, we observed no differences in treadmill endurance, grip strength, pain sensitivity, nerve conduction velocity, gastrocnemius diameter, or cardiac function, suggesting an underlying metabolic cause. During treadmill exercise, T10I mice exhibited reduced oxygen consumption, increased respiratory exchange ratio, and impaired lipolysis, with blunted increases in circulating glycerol and non-esterified fatty acids following β3-adrenergic stimulation. Reduced energy expenditure was also observed in aged R482Q mice with endurance exercise. Together, these findings demonstrate that mice with T10I or R482Q Lmna variants do not develop lipodystrophy, but have reduced voluntary running, in part due to disrupted energy regulation and adipose function. Further investigation of species-specific differences and compensatory mechanisms will be required.

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