Objective The relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in the context of obesity, and the correlation of these tissue-based phenomena with systemic metabolic disease are poorly defined. The goal of this study was to define clarify the relationship between adipose tissue fibrosis, adipocyte hypertrophy, and preadipocyte hyperplasia in human obesity and determine the correlation of these adipose-tissue based phenomena with diabetes. Methods Visceral and subcutaneous adipose tissues from humans with obesity collected during bariatric surgery were studied with QRTPCR, immunohistochemistry, and flow cytometry for expression of collagens and fibrosis-related proteins, adipocyte size, and preadipocyte frequency. Results were correlated with clinical characteristics including diabetes status. Results Fibrosis was decreased, hypertrophy was increased, and preadipocyte frequency and fibrotic gene expression were decreased in adipose tissues from diabetic subjects compared to non-diabetic subjects. These differences were greater in visceral compared to subcutaneous adipose tissue. Conclusions These data are consistent with the hypothesis that adipose tissue fibrosis in the context of human obesity limits adipocyte hypertrophy and is associated with a reciprocal increase in adipocyte hyperplasia, with beneficial effects on systemic metabolism. These findings suggest adipose tissue fibrosis as a potential target for manipulation of adipocyte metabolism.

Mitochondrial calcium uptake stimulates bioenergetics and drives energy production in metabolic tissue. It is unknown how a calcium-mediated acceleration in matrix bioenergetics would influence cellular metabolism in glycolytic cells that do not require mitochondria for ATP production. Using primary human endothelial cells (ECs), we discovered that repetitive cytosolic calcium signals (oscillations) chronically loaded into the mitochondrial matrix. Mitochondrial calcium loading in turn stimulated bioenergetics and a persistent elevation in NADH. Rather than serving as an impetus for mitochondrial ATP generation, matrix NADH rapidly transmitted to the cytosol to influence the activity and expression of cytosolic sirtuins, resulting in global changes in protein acetylation. In endothelial cells, the mitochondrion-driven reduction in both the cytosolic and mitochondrial NAD ؉ / NADH ratio stimulated a compensatory increase in SIRT1 protein levels that had an anti-inflammatory effect. Our studies reveal the physiologic importance of mitochondrial bioenergetics in the metabolic regulation of sirtuins and cytosolic signaling cascades.

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ObjectiveNK cells are understudied in the context of metabolic disease and obesity. The goal of this study was to define the effect of NK cell ablation on systemic inflammation and glucose homeostasis in murine obesity.MethodsA transgenic murine model was used to study the effect of NK cell ablation on systemic inflammation and glucose homeostasis in the context of diet-induced obesity using flow cytometry, QRTPCR, and glucose tolerance and insulin sensitivity testing.ResultsNK cell ablation achieved a 3-4 fold decrease in NK cells but had no effect on T-cell levels in adipose tissues and spleen. NK cell ablation was associated with decreased total macrophage infiltration in intra-abdominal adipose tissue, but macrophage infiltration in subcutaneous adipose tissue and spleen was unaffected. NK cell ablation was associated with modest improvement in insulin sensitivity but had no effect on tissue transcript levels of inflammatory cytokines.ConclusionNK cells play a role in promoting intra-abdominal adipose tissue macrophage infiltration and systemic insulin resistance in obesity.