Partial removal of visceral epididymal white adipose tissue in obese Ldlr-/-.Leiden mice alters adipokine secretion and improves cerebrovascular health

Visceral white adipose tissue (WAT) dysfunction is thought to contribute to obesity-related brain impairments but no causal relationship has been demonstrated yet. We herein investigated the impact of visceral epididymal WAT (eWAT) lipectomy on brain health and obesity-associated comorbidities (liver steatosis, atherosclerosis, WAT dysfunction) in obese Ldlr-/-.Leiden mice. To do so, high-fat diet (HFD)-fed mice with manifest obesity underwent sham surgery or partial removal (~70%) of eWAT. A separate group of mice was kept on chow diet (control). Liver disease, atherosclerosis and three WAT depots were examined histologically, and WAT biopsies were also used for <i>ex vivo</i> culture experiments. Brain structure and function were monitored longitudinally using neuroimaging and cognitive tests. Brain pathology was further analyzed using histological analyses and hippocampal RNA sequencing. The portion of eWAT depot which was surgically removed appeared to secrete multiple adipokines and pro-inflammatory factors <i>ex vivo</i>. Histological analyses at the end of the study showed that partial eWAT lipectomy had no effect on the development of liver pathology and atherosclerosis, but it reduced the number of severely hypertrophic adipocytes in the residual-eWAT. This was consistent with reduced secretion of adipokines (e.g., leptin, adiponectin) and pro-inflammatory mediators (e.g., PAI-1, MIP-1α, IL-17) in <i>ex vivo</i> residual-eWAT culturing experiments. Importantly, partial eWAT lipectomy also alleviated HFD-induced adverse effects on hippocampal vasoreactivity, increased cortico-hippocampal (resting-state) functional connectivity and prevented the development of sedentary behavior. Hence, partial eWAT lipectomy in mice with manifest obesity partly prevents hippocampal cerebrovascular disturbances, demonstrating a causal involvement of visceral WAT in obesity-associated brain impairments. The beneficial effects of eWAT lipectomy may, at least partly, be mediated by the observed changes in the release of adipokines and inflammatory mediators.

内脏白色脂肪组织（visceral white adipose tissue, WAT）功能异常被认为与肥胖相关脑损伤（obesity-related brain impairments）存在关联，但二者间的因果关系尚未得到证实。本研究旨在探讨内脏附睾白色脂肪组织（epididymal WAT, eWAT）脂肪切除术（lipectomy）对肥胖型Ldlr-/-.Leiden小鼠脑健康及肥胖相关共病（obesity-associated comorbidities，涵盖肝脂肪变性（liver steatosis）、动脉粥样硬化（atherosclerosis）及WAT功能异常）的影响。为此，我们对已出现明显肥胖的高脂饮食（high-fat diet, HFD）喂养小鼠实施假手术（sham surgery）或附睾白色脂肪组织部分切除术（切除比例约70%）；另有一组小鼠维持普通饲料饮食（chow diet），作为对照。通过组织学方法检测肝脏病变、动脉粥样硬化情况及三处白色脂肪组织储库；同时取脂肪组织活检样本开展离体（ex vivo）培养实验。采用神经影像学（neuroimaging）检查与认知测试（cognitive tests）对小鼠脑结构与功能进行纵向监测，并通过组织学分析及海马RNA测序（hippocampal RNA sequencing）进一步解析脑病理变化。
手术切除的附睾白色脂肪组织储库在离体培养中可分泌多种脂肪因子（adipokines）与促炎因子（pro-inflammatory factors）。研究终点的组织学分析显示，附睾白色脂肪组织部分切除术未对肝脏病变及动脉粥样硬化的进展产生影响，但可减少残余附睾白色脂肪组织中重度肥大脂肪细胞（hypertrophic adipocytes）的数量，这与离体培养实验中残余附睾白色脂肪组织分泌的脂肪因子（如瘦素（leptin）、脂联素（adiponectin））及促炎介质（如纤溶酶原激活物抑制剂-1（PAI-1）、巨噬细胞炎症蛋白1α（MIP-1α）、白细胞介素17（IL-17））水平降低的结果一致。尤为重要的是，附睾白色脂肪组织部分切除术还可缓解高脂饮食诱导的海马血管反应性异常，增强皮质-海马（静息态）功能连接，并阻止久坐行为（sedentary behavior）的发生。综上，在已出现明显肥胖的小鼠中实施附睾白色脂肪组织部分切除术，可部分预防海马脑血管紊乱（cerebrovascular disturbances），证实了内脏白色脂肪组织在肥胖相关脑损伤中的因果性作用。附睾白色脂肪组织切除术的有益效应，至少可部分通过上述脂肪因子与炎症介质释放的变化介导。