Secreted Human Adipose Leptin Decreases Mitochondrial Respiration in HCT116 Colon Cancer Cells

Obesity is a key risk factor for the development of colon cancer; however, the endocrine/paracrine/metabolic networks mediating this connection are poorly understood. Here we hypothesize that obesity results in secreted products from adipose tissue that induce malignancy-related metabolic alterations in colon cancer cells. Human HCT116 colon cancer cells, were exposed to conditioned media from cultured human adipose tissue fragments of obese vs. non-obese subjects. Oxygen consumption rate (OCR, mostly mitochondrial respiration) and extracellular acidification rate (ECAR, mostly lactate production via glycolysis) were examined vis-à-vis cell viability and expression of related genes and proteins. Our results show that conditioned media from obese (vs. non-obese) subjects decreased basal (40%, p) and maximal (50%, p) OCR and gene expression of mitochondrial proteins and Bax without affecting cell viability or expression of glycolytic enzymes. Similar changes could be recapitulated by incubating cells with leptin, whereas, leptin-receptor specific antagonist inhibited the reduced OCR induced by conditioned media from obese subjects. We conclude that secreted products from the adipose tissue of obese subjects inhibit mitochondrial respiration and function in HCT116 colon cancer cells, an effect that is at least partly mediated by leptin. These results highlight a putative novel mechanism for obesity-associated risk of gastrointestinal malignancies, and suggest potential new therapeutic avenues.肥胖是结直肠癌发生的关键风险因素，然而介导该关联的内分泌/旁分泌/代谢网络目前仍未被充分阐释。本研究提出如下假说：肥胖可促使脂肪组织分泌相关产物，进而诱导结直肠癌细胞产生与恶性表型相关的代谢改变。本研究将人源HCT116结直肠癌细胞暴露于分别源自肥胖与非肥胖受试者的体外培养脂肪组织碎片的条件培养基中，同步检测了细胞耗氧率（OCR，主要反映线粒体呼吸功能）与细胞外酸化率（ECAR，主要反映糖酵解途径的乳酸生成水平），并结合细胞活力及相关基因、蛋白的表达情况进行分析。本研究结果显示，相较于非肥胖受试者，肥胖受试者来源的条件培养基可使细胞基础耗氧率降低40%（p值）、最大耗氧率降低50%（p值），同时下调线粒体蛋白及Bax（Bcl-2-associated X protein）的基因表达，但不会影响细胞活力或糖酵解相关酶的表达。采用瘦素（leptin）直接孵育细胞可重现上述类似变化，而瘦素受体特异性拮抗剂可阻断肥胖受试者来源的条件培养基所诱导的耗氧率降低现象。本研究最终得出结论：肥胖受试者脂肪组织分泌的相关产物可抑制HCT116结直肠癌细胞的线粒体呼吸与功能，该效应至少部分由瘦素介导。本研究结果揭示了肥胖相关胃肠道恶性肿瘤风险的潜在全新机制，并为相关治疗策略的开发提供了新的潜在方向。