Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Bioinformatics Core Facility, National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Am J Physiol Endocrinol Metab. 2021 Nov 1;321(5):E702-E713. doi: 10.1152/ajpendo.00299.2021. Epub 2021 Oct 11.
In chronic obesity, activated adipose tissue proinflammatory cascades are tightly linked to metabolic dysfunction. Yet, close temporal analyses of the responses to obesogenic environment such as high-fat feeding (HFF) in susceptible mouse strains question the causal relationship between inflammation and metabolic dysfunction, and/or raises the possibility that certain inflammatory cascades play adaptive/homeostatic, rather than pathogenic roles. Here, we hypothesized that CTRP6, a C1QTNF family member, may constitute an early responder to acute nutritional changes in adipose tissue, with potential physiological roles. Both 3-days high-fat feeding (3dHFF) and acute obesity reversal [2-wk switch to low-fat diet after 8-wk HFF (8wHFF)] already induced marked changes in whole body fuel utilization. Although adipose tissue expression of classical proinflammatory cytokines (, , and ) exhibited no, or only minor, change, uniquely increased, and decreased, in response to 3dHFF and acute obesity reversal, respectively. CTRP6 knockout (KO) mouse embryonic fibroblasts (MEFs) exhibited increased adipogenic gene expression (, , and ) and markedly reduced inflammatory genes (, , and ) compared with wild-type MEFs, and recombinant CTRP6 induced the opposite gene expression signature, as assessed by RNA sequencing. Consistently, 3dHFF of CTRP6-KO mice induced a greater whole body and adipose tissue weight gain compared with wild-type littermates. Collectively, we propose CTRP6 as a gene that rapidly responds to acute changes in caloric intake, acting in acute overnutrition to induce a "physiological inflammatory response" that limits adipose tissue expansion. CTRP6 (C1qTNF6), a member of adiponectin gene family, regulates inflammation and metabolism in established obesity. Here, short-term high-fat feeding in mice is shown to increase adipose tissue expression of CTRP6 before changes in the expression of classical inflammatory genes occur. Conversely, CTRP6 expression in adipose tissue decreases early in the course of obesity reversal. Gain- and loss-of-function models suggest CTRP6 as a positive regulator of inflammatory cascades, and a negative regulator of adipogenesis and adipose tissue expansion.
在慢性肥胖中，激活的脂肪组织促炎级联反应与代谢功能障碍密切相关。然而，对易感性小鼠品系在肥胖环境（如高脂肪喂养（HFF））下的反应进行密切的时间分析，对炎症和代谢功能障碍之间的因果关系提出了质疑，或者提出了某些炎症级联反应可能发挥适应性/体内平衡作用，而不是致病作用的可能性。在这里，我们假设 CTRP6，一种 C1QTNF 家族成员，可能是脂肪组织对急性营养变化的早期反应者，具有潜在的生理作用。3 天高脂肪喂养（3dHFF）和急性肥胖逆转[8 周 HFF 后 2 周切换到低脂饮食（8wHFF）]已经引起了全身燃料利用的显著变化。虽然脂肪组织中经典促炎细胞因子（、和）的表达没有变化，或者只有轻微变化，但在 3dHFF 和急性肥胖逆转时分别显著增加和减少。CTRP6 敲除（KO）小鼠胚胎成纤维细胞（MEFs）表现出增加的脂肪生成基因表达（、和）和明显减少的炎症基因（、和）与野生型 MEFs 相比，而重组 CTRP6 通过 RNA 测序评估，诱导相反的基因表达特征。一致地，与野生型同窝仔相比，CTRP6-KO 小鼠的 3dHFF 诱导了更大的全身和脂肪组织体重增加。总之，我们提出 CTRP6 是一种快速响应热量摄入急性变化的基因，在急性营养过剩时诱导“生理性炎症反应”，从而限制脂肪组织扩张。CTRP6（C1qTNF6），一种脂联素基因家族的成员，在已建立的肥胖中调节炎症和代谢。在这里，在经典炎症基因表达发生变化之前，小鼠的短期高脂肪喂养显示增加了脂肪组织中 CTRP6 的表达。相反，在肥胖逆转过程的早期，脂肪组织中 CTRP6 的表达减少。获得和丧失功能的模型表明 CTRP6 是炎症级联的正调节剂，是脂肪生成和脂肪组织扩张的负调节剂。
