Omentectomy in the canine: a unique model to investigate the physiologic relationship between visceral fat and insulin action

Unrestricted Visceral obesity is associated with a variety of chronic diseases including type 2 diabetes and cardiovascular disease. A reduction in visceral fat by omentectomy improves the metabolic profile in humans, suggesting that visceral fat impairs insulin sensitivity (SI). We tested this hypothesis by examining the effects of omentectomy on metabolic function in non-obese dogs. Omentectomy failed to generate measurable changes in body weight (P=0.10), or subcutaneous adiposity (P=0.83). The removal of the greater omentum, which resulted in a diminutive 7% reduction in visceral fat (P=0.29), markedly enhanced SI 64% (P=0.03) particularly in peripheral tissues. These data provide compelling evidence for the deleterious role of visceral fat in insulin resistance, however the mechanism remains unclear.; Free fatty acids (FFA) have been suggested to mediate visceral obesity and insulin resistance. We examined 24-hour plasma profiles of FFA and adipokines to identify putative signal(s) that may modulate SI following omentectomy in obese dogs. Visceral fat was reduced 16% (P=0.005) and was accompanied by an 18% improvement in SI (P=0.01). Although we observed no variations in 24-hour adiponectin (P=0.58) or the inflammatory marker C-reactive protein (P=0.19), FFA were diminished at all times during the day resulting in a 22% reduction in area under the curve (P=0.03). Moreover, changes in FFA were correlated with SI improvements (P=0.03), suggesting that a reduction in FFA, not adipokines, modulate SI with reduced visceral fat. Thus, visceral fat-derived FFA may induce insulin resistance with truncal-obesity.; The effects of omentectomy have conflicting results in humans. To examine the efficacy of omentectomy as a long-term therapeutic option, omentectomized- and sham-treated dogs were challenged with a high-fat diet to determine relative susceptibility to obesity and insulin resistance. While there was no difference in the progression to insulin resistance between groups (P=0.72), omentectomized-dogs were unable to compensate with hyperinsulinemia (P=0.39), suggesting pancreatic beta-cell impairment. Hence, while omentectomy produces impressive short-term improvements in SI, results in the dog model suggest omentectomy will not provide enduring benefits for metabolic co-abnormalities of central-obesity in humans. Further studies are necessary to determine molecular role of the greater omentum in determination of SI, diurnal FFA, and β-cell compensation.无限制内脏型肥胖与多种慢性病相关，包括2型糖尿病与心血管疾病。通过网膜切除术减少内脏脂肪可改善人类的代谢谱，这提示内脏脂肪会损伤胰岛素敏感性（SI）。本研究通过检测网膜切除术对非肥胖犬代谢功能的影响，验证了这一假说。结果显示，网膜切除术未对体重（P=0.10）或皮下脂肪量（P=0.83）产生可检测到的变化。切除大网膜仅使内脏脂肪小幅减少7%（P=0.29），却显著提升了64%的胰岛素敏感性（P=0.03），该效应在外周组织中尤为明显。上述数据为内脏脂肪在胰岛素抵抗中的有害作用提供了有力证据，但其具体机制仍未阐明。 游离脂肪酸（FFA）被认为介导了内脏型肥胖与胰岛素抵抗的发生。本研究检测了24小时血浆游离脂肪酸与脂肪因子谱，以明确肥胖犬接受网膜切除术后可能调控胰岛素敏感性的潜在信号分子。研究中内脏脂肪减少了16%（P=0.005），同时胰岛素敏感性提升了18%（P=0.01）。尽管未观察到24小时脂联素（P=0.58）或炎症标志物C反应蛋白（P=0.19）出现显著变化，但全天血浆游离脂肪酸水平均有所降低，使其曲线下面积减少22%（P=0.03）。此外，游离脂肪酸的变化与胰岛素敏感性的改善呈显著相关（P=0.03），这提示内脏脂肪减少后，是游离脂肪酸而非脂肪因子调控了胰岛素敏感性。因此，内脏脂肪来源的游离脂肪酸可能通过躯干型肥胖诱导胰岛素抵抗。 网膜切除术在人类中的疗效存在争议。为探究网膜切除术作为长期治疗方案的有效性，本研究对接受网膜切除术与假手术的犬给予高脂饮食刺激，以明确二者在肥胖与胰岛素抵抗易感性上的差异。尽管两组在胰岛素抵抗进展方面无显著差异（P=0.72），但接受网膜切除术的犬无法通过高胰岛素血症进行代偿（P=0.39），这提示其胰腺β细胞功能受损。因此，尽管网膜切除术可在短期内显著改善胰岛素敏感性，但犬模型的研究结果提示，网膜切除术无法为人类中心型肥胖相关的代谢共病提供持久获益。未来仍需进一步研究以明确大网膜在调控胰岛素敏感性、昼夜游离脂肪酸水平以及β细胞代偿功能中的分子机制。