Dynamic regulation of circulating endotrophin by changes in fat mass in humans

BACKGROUND AND AIMS: During long-term weight gain, extracellular matrix remodeling in adipose tissue elevates local and systemic endotrophin, potentially contributing to metabolic dysfunction. Whether short-term increases or reductions in fat mass modulate circulating endotrophin concentrations in humans remains unclear. We aimed to determine the relationship between short-term changes in fat mass (kg and fat percentage points) and circulating endotrophin levels, and to explore whether endotrophin mediates the effects of adiposity on lipid profiles. METHODS: Secondary analysis of the pooled individual participant data from two clinical trials. One trial randomized 42 healthy adults (52.4% women, 26-49 years) to one of the following six-month interventions: (a) weight maintenance, (b) 25% caloric restriction, (c) 12.5% caloric restriction and 12.5% increased energy expenditure, or (d) very low-calorie diet. The other trial enrolled 31 healthy adults (19.4% women, 20-40 years) and exposed them to an eight-week 40% overfeeding. Fat mass, circulating endotrophin, and circulating lipid profile were measured before and after these interventions. RESULTS: Considering all participants, the changes in fat mass ranged from -11.0 to +7.0 kg or -9.6 to +5.7 percentage points. Changes in fat mass were positively associated with changes in circulating endotrophin (unstandardized B-coefficient [95% CI] = 0.76 [0.45, 1.07] ng/mL/kg and 0.89 [0.51, 1.28] ng/mL/percentage point, P < 0.001). Exploratory mediation analyses showed that endotrophin mediated 15% [4, 51] of the effect of fat mass on total cholesterol. CONCLUSION: Changes in fat mass, including loss and gain, are associated with corresponding changes in circulating endotrophin, which may partially mediate metabolic effects. Future studies should test whether endotrophin represents a therapeutic target for metabolic health in humans.