Mid Sweden University

Introduction

Leptin signals in skeletal muscles through pathways which share some steps with the insulin and IGF1. We have recently shown that LEPR (OBR-170) is increased in the dominant arm of tennis players ¹ and is reduced in deltoid and vastus lateralis (VL) of obese compared to control subjects ². The aim of this study was to determine whether exercise up-regulates the protein abundance and phosphorylation status of the different molecular variations of the LEPR (OBR-170, 128, 98A or 98B) in human skeletal muscle. We hypothesized that exercise will up-regulate leptin signaling in skeletal muscle.

Methods

Fifteen overweight men underwent three experimental phases: pre-test (PRE); caloric restriction (3.2 Kcal/kg body Wt/d) + exercise (45min unilateral arm cranking/d + 8h walking/d) for 4 days (CRE); and control isoenergetic diet + reduced exercise for 3 days (CD). During CRE, the diet consisted solely of whey protein (PRO, n=8) or sucrose (SU, n=7) (0.8 g/kg body Wt/d). Muscle biopsies (135 biopsies in all) were obtained from the trained and untrained deltoid, and VL, after 12h fast at PRE, and end of CRE and CD. The molecular variants of LEPR (OBR-170, 128, 98A and 98B) were determined by western blot and LEPR mRNA by PCR.

Results

Serum leptin was reduced by ~60% following CRE and CD (P<0.05). LEPRs were more abundant in arm than leg muscles. LEPR mRNA was increased in exercised muscles after CRE. OBR-170 was reduced after CRE and CD only in the control arm (P<0.05). OBR-128 was increased after CD in exercised extremities (P<0.05). OBR-98A was increased after CRE in trained arm, and after CD in legs (P<0.05). However, OBR-98B was increased after CRE and CD in both arms and exercised extremities (P<0.05), being these effects more pronounced in the PRO group (P<0.05). After CD, LEPR mRNA returned to basal levels while LEPR expression was increased in all muscles (P<0.05). The fraction of LEPR activated (Tyr1141 phosphorylated) was reduced in arms but not in leg muscles. LEPR phosphorylation was correlated with JAK2 (upstream) and STAT3 (downstream) phosphorylation (r=0.67-0.89, P<0.05).

Discussion

Caloric restriction seems to reduce the abundance of LEPR, but this effect varies depending on specific molecular variants of the receptor. The reduction of LEPR is partly counteracted by exercise, likely contributing to increase muscle leptin sensitivity. Whey protein ingestion facilitates these effects. Resuming normal food ingestion after a period of severe energy deficit is accompanied by increased expression LEPR in skeletal muscle.