ObjectiveObesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM). This study investigated whether impaired adipogenesis of omental (OM) adipose tissues and elevated 4-hydroxynonenal (4-HNE) accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype.MethodsOM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery. Levels of 4-HNE protein adducts, adipocyte size and number of macrophages were determined within these tissues by immunohistochemistry. Adipogenic capacity and gene expression profiles were assessed in preadipocytes derived from these tissues in relation to insulin resistance and in response to 4-HNE, metformin or combined metformin and insulin treatment.ResultsPreadipocytes isolated from insulin resistant (IR) and T2DM individuals exhibited lower adipogenesis, marked by upregulation of anti-adipogenic genes, compared to preadipocytes derived from insulin sensitive (IS) individuals. Impaired adipogenesis was also associated with increased 4-HNE levels, smaller adipocytes and greater macrophage presence in the adipose tissues. Within the T2DM group, preadipocytes from combined metformin and insulin treated subset showed better in vitro adipogenesis compared to metformin alone, which was associated with less presence of macrophages and 4-HNE in the adipose tissues. Treatment of preadipocytes in vitro with 4-HNE reduced their adipogenesis and increased proliferation, even in the presence of metformin, which was partially rescued by the presence of insulin.ConclusionThis study reveals involvement of 4-HNE in the impaired OM adipogenesis-associated with insulin resistance and T2DM and provides a proof of concept that this impairment can be reversed by the synergistic action of insulin and metformin. Further studies are needed to evaluate involvement of 4-HNE in metabolically impaired abdominal adipogenesis and to confirm benefits of combined metformin-insulin therapy in T2DM patients.

Aims: Obesity is a risk factor for endothelial dysfunction, the severity of which is likely to vary depending on extent and impact of adiposity on the vasculature. This study investigates the roles of cyclooxygenase isoforms and thromboxane receptor activities in the differential endothelial dilatory capacities of arteries derived from omental and subcutaneous adipose tissues in obesity. Main methods: Small arteries were isolated from omental and subcutaneous adipose tissues obtained from consented morbidly obese patients (n=65, BMI 45±6 Kg.m-2 [Mean±SD]) undergoing bariatric surgery. Relaxation to acetylcholine was studied by wire myography in the absence or presence of indomethacin (10 µM, cyclooxygenase inhibitor), FR122047 (1 µM, cyclooxygenase-1 inhibitor), Celecoxib (4 µM, cyclooxygenase-2 inhibitor), Nω-Nitro-L-arginine methyl ester (L-Name, 100 µM, nitric oxide synthase inhibitor) or combination of apamin (0.5 µM) and charybdotoxin (0.1 µM) that together inhibit endothelium-derived hyperpolarizing factor (EDHF). Contractions to U46619 (thromboxane A2 mimetic) were also studied. Key findings: Acetylcholine relaxation was significantly attenuated in omental compared with subcutaneous arteries from same patients (p˂0.01). Indomethacin (p<0.01) and FR122047 (p<0.001) but not Celecoxib significantly improved the omental arteriolar relaxation. Cyclooxygenase-1 mRNA and U46619 contractions were both increased in omental compared with subcutaneous arteries (p˂0.05). L-Name comparably inhibited acetylcholine relaxation in both arteries, while apamin+charybdotoxin were less effective in omental compared with subcutaneous arteries. Significance: The results show that the depot-specific reduction in endothelial dilatory capacity of omental compared with subcutaneous arteries in obesity is in large part due to altered cyclooxygenase-1 and enhanced thromboxane receptor activities, which cause EDHF deficiency.

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Background: Recent trends suggest that the sharpest increases in the prevalence of obesity are in countries of the Middle East, especially in Qatar. Early and rapid onset of the disease in this population, along with a primarily abdominal omental deposition of adipose tissue, is closely associated with insulin resistance, whilst longer duration of obesity in Caucasians is associated with maintenance of insulin sensitivity, independently of BMI. The impact of more aggressive treatments for obesity, such as surgery, on the metabolic health of the Qataris is not known. Objectives: To test the hypothesis that inherent differences between the Qataris and Caucasians in adipose tissue secretory function and sensitivity to insulin determines their response to interventions that reduce their adipose tissue mass. Methods: Non-diabetic morbidly obese subjects were recruited from Qatari and Caucasian patients awaiting weight reduction surgery (Al-Emadi Hospital, Doha, Qatar and Whittington Hospital, London, UK). Anthropometric measures were recorded. Blood samples were obtained before, and in a sub-set after weight loss for determination of lipids, glucose, insulin and adipokines. Insulin resistance was measured by HOMA. Results: The Qataris were significantly younger (p=0.005), despite having comparable BMI (Qatari 47.7±7.0; Caucasian 48.4±7.6 kg/m-2, p=0.70). They also had lower diastolic blood pressure and a better lipid profile. However, the Qataris had significantly higher insulin and HOMA index of insulin resistance, and higher leptin and interleukin-6. Also, in Qataris, leptin was negatively correlated with a number of risk factors for metabolic syndrome, independent of BMI. However, these correlations seem to be BMI-dependent in Caucasians. Further, weight loss in Caucasians did not significantly change insulin sensitivity but did reduce dyslipidemia. While in Qataris, characterized by high insulin resistance, weight loss causes sharp reduction in insulin resistance but not in dyslipidemia. Conclusion: Obesity in Qatari subjects was accompanied by a higher degree of hyperinsulinaemia and hyperleptinaemia compared to Caucasians. The nature of obesity and high insulin resistance in Qataris makes it amenable to aggressive weight loss treatment, whereas in Caucasians other less aggressive treatments for obesity may be applicable.