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

Abstract

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.