Partial removal of visceral epididymal white adipose tissue in obese Ldlr-/-.Leiden mice impacts adipokine secretion, plasma free fatty acids, and improves cerebrovascular health

Visceral white adipose tissue (WAT) dysfunction may contribute to obesity-related brain impairments but causal relationship has not been demonstrated. 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. High-fat diet (HFD)-fed obese mice 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 cultured ex vivo. Brain structure and function were monitored longitudinally using cognitive tests and neuroimaging, paralleled by histological analysis of brain pathology and hippocampal RNA-sequencing. In ex vivo WAT culture, the surgically removed eWAT portion secreted many adipokines and pro-inflammatory factors. Histological analyses at the end of the study showed that eWAT-lipectomy did not affect liver disease and atherosclerosis development, but 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/CCL3, IL-17) from the residual-eWAT in the ex vivo culturing experiments. Importantly, lipectomy alleviated HFD-induced adverse effects on hippocampal vasoreactivity, increased cortico-hippocampal (resting-state) functional connectivity and prevented the development of sedentary behavior. Lipectomy did not significantly affect histological neuroinflammation or circulating cytokines/chemokines, but increased specific free fatty acids (e.g., eicosatrienoic acid and docosahexaenoic acid, known to have anti-inflammatory and vaso-protective properties). 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 anti-inflammatory free fatty acids, and possible changes in release of adipokines and inflammatory mediators.