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

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.

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.

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.

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.