Insulin and Body Mass Index Decrease Serum Soluble Leptin Receptor Levels in Humans

Abstract

Context: Serum soluble leptin receptor (sOb-R) may protect against future type 2 diabetes or serve as a marker for protective features, but how sOb-R is regulated is largely unknown.

Objective: This work aimed to test how serum sOb-R is influenced by glucose, insulin, body fat, body mass index (BMI), food intake, and physical activity.

Methods: We performed an epidemiological triangulation combining cross-sectional, interventional, and Mendelian randomization study designs. In 5 independent clinical studies (n = 24-823), sOb-R was quantified in serum or plasma by commercial enzyme-linked immunosorbent assay kits using monoclonal antibodies. We performed mixed-model regression and 2-sample Mendelian randomization.

Results: In pooled, cross-sectional data, leveling by study, sOb-R was associated inversely with BMI (β [95% CI] -0.19 [-0.21 to -0.17]), body fat (-0.12 [-0.14 to -0.10), and fasting C-peptide (-2.04 [-2.46 to -1.62]). sOb-R decreased in response to acute hyperinsulinemia during euglycemic glucose clamp in 2 independent clinical studies (-0.5 [-0.7 to -0.4] and -0.5 [-0.6 to -0.3]), and immediately increased in response to intensive exercise (0.18 [0.04 to 0.31]) and food intake (0.20 [0.06 to 0.34]). In 2-sample Mendelian randomization, higher fasting insulin and higher BMI were causally linked to lower sOb-R levels (inverse variance weighted, -1.72 [-2.86 to -0.58], and -0.20 [-0.36 to -0.04], respectively). The relationship between hyperglycemia and sOb-R was inconsistent in cross-sectional studies and nonsignificant in intervention studies, and 2-sample Mendelian randomization suggested no causal effect of fasting glucose on sOb-R.

Conclusion: BMI and insulin both causally decreased serum sOb-R levels. Conversely, intensive exercise and food intake acutely increased sOb-R. Our results suggest that sOb-R is involved in short-term regulation of leptin signaling, either directly or indirectly, and that hyperinsulinemia may reduce leptin signaling.

Keywords: hyperglycemia; hyperinsulinemia; leptin signaling; obesity; soluble leptin receptor.

Figure 1.

Serum soluble leptin receptor (sOb-R) during glucose clamp in 2 independent clinical studies: A, DIVINE (n = 61), and B, DIPI (n = 39). Data represent β and 95% CIs from mixed-model regression. A: F, fasted state; 2 hours, after 2 hours of tracer; HG, hyperglycemia (during intravenous glucose tolerance test, right before clamp); HI, hyperinsulinemia (end of clamp). B: F, fasted state; HI, physiological hyperinsulinemia (end of first step of clamp, 40 mU/m²/min insulin infusion); HI+, supraphysiological hyperinsulinemia (end of second step of clamp, 400 mU/m²/min insulin infusion).

Figure 2.

Changes during food intake in A, serum soluble leptin receptor (sOb-R); B, insulin; C, glucose; D, leptin (n = 39), and change in E, plasma sOb-r, and F, plasma leptin during acute intensive exercise (45 min 70% of maximal oxygen uptake) (n = 26). Data are β and 95% CI from mixed-model regression. Food and bicycle images: Flaticon.com.