Adipose tissue macrophage populations and inflammation are associated with systemic inflammation and insulin resistance in obesity

Abstract

Obesity is accompanied by numerous systemic and tissue-specific derangements, including systemic inflammation, insulin resistance, and mitochondrial abnormalities in skeletal muscle. Despite growing recognition that adipose tissue dysfunction plays a role in obesity-related disorders, the relationship between adipose tissue inflammation and other pathological features of obesity is not well-understood. We assessed macrophage populations and measured the expression of inflammatory cytokines in abdominal adipose tissue biopsies in 39 non-diabetic adults across a range of body mass indexes (BMI 20.5-45.8 kg/m2). Skeletal muscle biopsies were used to evaluate mitochondrial respiratory capacity, ATP production capacity, coupling, and reactive oxygen species production. Insulin sensitivity (SI) and beta cell responsivity were determined from test meal postprandial glucose, insulin, c-peptide, and triglyceride kinetics. We examined the relationships between adipose tissue inflammatory markers, systemic inflammatory markers, SI, and skeletal muscle mitochondrial physiology. BMI was associated with increased adipose tissue and systemic inflammation, reduced SI, and reduced skeletal muscle mitochondrial oxidative capacity. Adipose-resident macrophage numbers were positively associated with circulating inflammatory markers, including tumor necrosis factor-α (TNFα) and C-reactive protein (CRP). Local adipose tissue inflammation and circulating concentrations of TNFα and CRP were negatively associated with SI, and circulating concentrations of TNFα and CRP were also negatively associated with skeletal muscle oxidative capacity. These results demonstrate that obese humans exhibit increased adipose tissue inflammation concurrently with increased systemic inflammation, reduced insulin sensitivity, and reduced muscle oxidative capacity, and suggest that adipose tissue and systemic inflammation may drive obesity-associated metabolic derangements.

Impact of obesity on the molecular response to a single bout of exercise in a preliminary human cohort

“…Although exercise leads to many favorable adaptations and represents an important behavioral strategy to lessen the burden of obesity, the notable variability in exercise responsiveness (10) Gene-centric GSEA identified downregulation of numerous gene sets in individuals with obesity, including "Fatty Acid Metabolism," "Citric Acid Cycle," "Oxidative Phosphorylation," and "Respiratory Electron Transport." These gene sets also emerged as significantly downregulated in muscle in individuals with obesity by global proteomics and they are consistent with literature that has demonstrated that mitochondrial function is impaired with obesity (16) and that it may be linked with insulin resistance (26). Other notably downregulated gene sets were relevant to muscle protein synthesis, including "Translation," "Mitochondrial Protein Import," "Mitochondrial Translation," "Complex I Biogenesis," "Ribosome,"…”

“…A muscle biopsy was performed on the exercised leg 3.5 hours following completion of the exercise bout. The 2‐day inpatient period, with resting and postexercise biopsies performed on separate days, was required to accommodate the additional outcomes pertinent to the aims of the parent project, some of which have been published previously (16) and others which are ongoing.…”

“…Muscle samples from four lean adults (BMI: 22 [2] kg/m 2 ; two male and two female individuals) and four adults with obesity (BMI: 39 [3]; four female individuals) were analyzed from a previously published study (16). Participants were recruited from Southeast Minnesota.…”

Role of Adipose Tissue Derived Exosomes in Metabolic Disease

“…There is increasing evidence that adipose tissue-derived exosomes not only function in paracrine and endocrine modes, but also act as intercellular communicators to facilitate the transition of adipocytes towards maturity ( 43 ). In studies of the role of exosomes in systemic metabolism, adipocyte-derived exosomes were found to be mediators linking obesity and insulin resistance in surrounding tissues such as the liver, interacting with adjacent sites to promote lipid esterification ( 44 , 45 ). Connolly et al.…”

Ginsenoside compound K inhibits obesity-induced insulin resistance by regulation of macrophage recruitment and polarization via activating PPARγ

“…Then the increase of free fatty acids in adipose tissue causes the release of reactive oxygen species, which in turn causes oxidative stress or hypoxia in tissues, and finally makes the body present a state of systemic low-grade inflammation. 3,4 Inflammatory factors reduce the insulin sensitivity of muscle, fat and other tissues by affecting the insulin signaling pathway, thus causing IR. 5 For example, TNF-α could inhibit tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) through activating the ERK and JNK inflammatory pathways, resulting in the inhibition of glucose uptake.…”