Role of adipose tissue macrophages in the cross-talk between visceral adipose tissue and heart during high fat diet

Obesity is associated with remodeled and dysfunctional visceral white adipose tissue (vWAT). Recent studies suggest a cross-talk between vWAT and heart contributing to cardiac abnormalities. We hypothesized that adipose tissue macrophages (ATM) play a key role in the vWAT remodeling through a mechanism of premature senescence in high fat diet (HFD)-induced obesity. Establish the chronological order of events leading to vWAT premature senescence in the context of obesity and figure out the role of senescent ATM in the cross-talk between vWAT and heart. Two-month-old C57BL/6 male mice (n = 5/group) fed with HFD (60% fat, 7% sucrose) or chow diet (CD) for 2, 5, or 10 weeks underwent in vivo cardiac evaluation (echocardiography) and metabolic tests (glucose and insulin tolerance tests). Myocardial fibrosis, vWAT remodeling, ATM infiltration (CD68), senescence (p16 and p21) and inflammation were assessed. Body weight gain induced by HFD diverged from CD (CD: 29.6 ± 0.5 vs HFD: 35.0 ± 1.3, P < 0.01) after 5 weeks. Even preceding this, mice showed glucose intolerance and insulin resistance. These changes paralleled vWAT remodeling, i.e. increase in adipocyte size, ATM infiltration, and appearance of crown-like structures, a phenomenon of inflammatory adipocyte death. Classic pro-inflammatory markers, other than those involved in macrophage recruitment were unchanged. Two weeks of HFD sufficed to induce ATM senescence (p16 and p21). Myocardial function evaluated by strain rate was compromised by HFD as early as 2 weeks of diet (CD: 33.2 ± 1.2 vs HFD: 28.4 ± 0.2, P < 0.01). This was later followed by myocardial interstitial fibrosis. HFD disturbed glucose homeostasis, induced ATM senescence and myocardial dysfunction prior to body weight gain. These alterations preceded major inflammation and fibrotic remodeling both in vWAT and heart.