Leptin-Melanocortin pathway variants and gastric emptying in patients with obesity

Abstract

Background: Accelerated gastric emptying (GE) is a trait seen in obesity. Mutations in the hypothalamic leptin-melanocortin 4 receptor (Leptin-MC4R) pathway have been associated with obesity. We sought to investigate the association of leptin-MC4R pathway variants and GE in patients with obesity.

Methods: This is a cross-sectional study of patients with a history of severe obesity that were genotyped and completed a GE test by scintigraphy. We evaluated the percentage of GE (GE %) at 2 and 4 h between both groups using ANCOVA with weight and sex as covariates. We subdivide patients into carriers based on the location of the identified variants (i.e., upstream or downstream of the Leptin-MC4R pathway) and compared them with noncarriers using ANOVA. Results are presented as mean and standard deviation (± SD).

Key results: A total of 95 patients; nine carriers (67% females; 39.78 ± 12.33 years; BMI: 49.14 ± 12.96 kg/m2) and 86 noncarriers (87% female; 49.98 ± 13.74 years; BMI: 40.75 ± 6.29 kg/m2) were included. At 2 and 4 h, carriers had a delayed GE when compared noncarriers (p = 0.03 and p = 0.005, respectively). In carriers, when compared upstream carriers vs. downstream carriers vs. noncarriers by location there was a significant difference in GE among groups at 2 h and at 4 h (p = 0.02 and p = 0.01, respectively).

Conclusions & inferences: Carriers of heterozygous variants in the Leptin-MC4R pathway had a delayed GE compared to noncarriers. These findings point the important relationship between the Leptin-MC4R pathway and gastric motility.

Keywords: accelerated gastric emptying; leptin‐MC4R pathway; obesity.

Figure 1:. Diagram illustrating the components of the Leptin-Melanocortin Pathway and interactions in Food Intake Regulation.

The hypothalamic leptin-melanocortin pathway responds to peripheral signals, notably leptin, PYY, GLP-1, and insulin, to control food intake. Leptin, released by adipose tissue, activates POMC neurons, initiating an anorexigenic signal cascade. This cascade triggers the melanocortin system via α-MSH and MC4R, reducing food intake. In contrast, ghrelin activates AgRP and NPY neurons, which inhibit the melanocortin system and stimulate food intake.

Figure 2.

Consort flow

Figure 3.

A) Gastric emptying curve by carrier status shown as mean and standard error of the mean. B) Gastric emptying curve by carrier variant location (upstream or downstream) compare with non-carries. In dotted lines is shown the half-gastric emptying time.