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Adipose Tissue_Appetite_and Obesity

ORF18-03 - Skeletal Muscle, Adipocyte, and Hepatocyte-Autonomous Roles of the Activin Type II Receptors in the Regulation of Body Weight During Obesity

Saturday, June 13, 2026
3:40 PM - 3:45 PM CT
Location: Room W184ABC
Incretin-based drugs lead to weight loss via reductions in both fat and muscle mass. The Activin Type IIA and IIB receptors (ActRIIA/B) are targets of interest to mitigate this loss of muscle mass. Systemic blockade of ActRIIA/B prevents binding of TGF-β family ligands, resulting in muscle hypertrophy and reduced adiposity. Increased levels of circulating Activin E, a liver-derived TGF-β ligand, have been associated with unfavorable fat distribution. The objective of our study is to isolate the cell-autonomous roles of inhibiting ActRIIA/B in muscle, adipose tissue, and the liver in the regulation of body composition during obesity.

Tissue-specific knockout models were generated by crossing Acvr2aloxp/loxp; Acvr2bloxp/loxp mice to those carrying a muscle- or adipocyte- specific Cre recombinase (HSA or Adiponectin Cre) or administered an adeno-associated virus containing liver-specific Cre (AAV8-TBG-Cre). Male and female mice were fed a 60 kcal% diet for 8-12 weeks, with body composition and metabolic parameters assessed throughout. After 12 weeks, the liver, fat depots, and hindlimb muscles were collected. ANOVA or t-tests were performed; significance determined as p < 0.05.

Skeletal muscle-specific deletion of ActRIIA/B resulted in muscle hypertrophy and protection from gain of fat mass, while adipocyte-specific deletion had no effect on body composition. ActRIIA/B deletion in the liver reduced adipose tissue mass and elevated lipolysis. Our data suggest that this can be attributed to lower hepatic Inhbe expression and circulating Activin E. Our findings suggest that inhibition of cell-autonomous ActRIIA/B signaling in skeletal muscle and the liver, but not adipose tissue, drives changes in body composition during obesity.

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