Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans

Abstract

Intermuscular adipose tissue (IMAT) is negatively related to insulin sensitivity, but a causal role of IMAT in the development of insulin resistance is unknown. IMAT was sampled in humans to test for the ability to induce insulin resistance in vitro and characterize gene expression to uncover how IMAT may promote skeletal muscle insulin resistance. Human primary muscle cells were incubated with conditioned media from IMAT, visceral (VAT), or subcutaneous adipose tissue (SAT) to evaluate changes in insulin sensitivity. RNAseq analysis was performed on IMAT with gene expression compared with skeletal muscle and SAT, and relationships to insulin sensitivity were determined in men and women spanning a wide range of insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Conditioned media from IMAT and VAT decreased insulin sensitivity similarly compared with SAT. Multidimensional scaling analysis revealed distinct gene expression patterns in IMAT compared with SAT and muscle. Pathway analysis revealed that IMAT expression of genes in insulin signaling, oxidative phosphorylation, and peroxisomal metabolism related positively to donor insulin sensitivity, whereas expression of macrophage markers, inflammatory cytokines, and secreted extracellular matrix proteins were negatively related to insulin sensitivity. Perilipin 5 gene expression suggested greater IMAT lipolysis in insulin-resistant individuals. Combined, these data show that factors secreted from IMAT modulate muscle insulin sensitivity, possibly via secretion of inflammatory cytokines and extracellular matrix proteins, and by increasing local FFA concentration in humans. These data suggest IMAT may be an important regulator of skeletal muscle insulin sensitivity and could be a novel therapeutic target for skeletal muscle insulin resistance.

Gut Microbial, Inflammatory and Metabolic Signatures in Older People with Physical Frailty and Sarcopenia: Results from the BIOSPHERE Study

“…On the other hand, reduced SCFA production may trigger insulin resistance and result in increased fatty acid deposition within the muscle. The ensuing lower muscle quality may further promote insulin resistance, feeding a vicious circle that contributes to the onset and progression of PF&S [51,52]. Whether and how Ruminococcus and Oscillospira abundance impacts muscle metabolism and function in the context of PF&S warrants further investigation.…”

Role of Metabolic Stress and Exercise in Regulating Fibro/Adipogenic Progenitors

“…Although not yet directly tested, the local accumulation of intermuscular adipose tissue may impair muscle metabolism by producing high intramuscular concentrations of adipokines, adipose-derived hormones, and free fatty acids. In support of this notion, some studies have reported positive correlations between intermuscular adipose tissue accumulation and the decrease in insulin sensitivity observed during aging and obesity (Goodpaster et al, 1997(Goodpaster et al, , 2000Ryan and Nicklas, 1999;Sachs et al, 2019). Interestingly, the majority of studies on intermuscular adipose tissue accumulation under conditions of metabolic stress have been conducted in humans.…”

Associations of Thigh and Abdominal Adipose Tissue Radiodensity with Glucose and Insulin in Nondiabetic African‐Ancestry Men

“…Skeletal muscle, which is insulin sensitive, was shown to be found in larger quantities in the thigh compared with the abdomen . The location of IMAT next to skeletal muscle suggests a role for IMAT in insulin resistance; indeed, IMAT‐secreted factors were shown to reduce insulin sensitivity in myotubes in vitro , and thigh IMAT volume is positively associated with both insulin resistance and risk of T2D independent of overall obesity . There are also racial/ethnic differences in regional IMAT distribution, with studies reporting greater thigh and calf IMAT in African‐ancestry individuals compared with Caucasians , as opposed to similar or lower levels of abdominal IMAT.…”