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The genomic CDKN2A/B locus, encoding p16INK4a among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16INK4a is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16INK4a knock-down in 3T3/L1 preadipocytes or p16INK4a deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16INK4a in adipose tissue formation. p16INK4a-deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16INK4a-deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16INK4a-deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16INK4a gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16INK4a modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

BACKGROUND Although neutrophils are crucially involved in inflammation, they have received only little attention in metabolic syndrome (MetS). We hypothesized that neutrophil infiltration into adipose tissue (AT) may occur at an early stage of MetS, in association with modulation of major functions of neutrophils and of their bone marrow production. METHODS Fifty-six male Sprague-Dawley rats were fed regular (control rats (CRs)) or high-fructose (60%; fructose-fed rats (FFRs)) diets. After 6 weeks, metabolic parameters were measured. Distribution of neutrophils into AT was investigated by immunohistochemistry. Function of circulating neutrophils (activation, reactive oxygen species production, phagocytosis, and apoptosis) was determined by flow cytometry. Granulopoiesis was evaluated by measuring the number and survival characteristics of neutrophil progenitors using bone marrow culture assays and flow cytometry. RESULTS Compared with the CR group, the FFR group developed MetS (i.e., arterial hypertension, hypertriglyceridemia, fasting hyperglycemia, and greater intra-abdominal AT volume) and presented higher neutrophil infiltration into AT. At resting state, no significant difference for circulating neutrophil functions was observed between the 2 groups. In contrast, circulating neutrophils from the FFR group exhibited higher responses to phorbol-12-myristate-13-acetate for all studied functions, compared with the CR group, suggesting that early MetS induces neutrophil priming. In parallel, a diminished clonal capacity and an increased apoptosis in bone marrow–derived granulocyte progenitors and neutrophil precursors were observed in the FFR group compared with the CR group. CONCLUSIONS These results provide evidence of an increased infiltration into intra-abdominal AT and modified production, function, and phenotype of neutrophils at an early stage of high-fructose diet–induced MetS. [ABSTRACT FROM AUTHOR]

The genomic CDKN2A/B locus, encoding p16 INK4a among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16 INK4a is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16 INK4a knock-down in 3T3/L1 preadipocytes or p16 INK4a deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16 INK4a in adipose tissue formation. p16 INK4a -deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16 INK4a -deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16 INK4a -deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16 INK4a gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16 INK4a modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk.