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 ex vivo 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 ex vivo. 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 ex vivo 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.