Beige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice

De-Huang Guo,Masaki Yamamoto,Hesam Khodadadi,Caterina M Hernandez,Alexis M Stranahan,Babak Baban

doi:10.1038/s41467-021-24540-8

De-Huang Guo, Masaki Yamamoto + Show 4 more

Open Access

https://doi.org/10.1038/s41467-021-24540-8

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Abstract

Visceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.

Highlights

Visceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not
Weight gain was similar in Tg and nontransgenic littermate controls (nTg) mice over 4 wk (Fig. 1a), and the proportional weights of subcutaneous adipose tissue (SAT), epididymal visceral adipose tissue (VAT), and interscapular brown adipose tissue (BAT) did not differ between genotypes (Fig. 1b)
After observing increases in CSF IL4 and accumulation of CNS T cells in SAT transplant recipients, we considered the following scenarios: first, lymphocytes from the SAT donor could be trafficking into the CNS; and second, lymphocytes from the recipient could interact with beige adipocytes in a manner that enhances cognition and reduces neuroinflammation

Summary

Introduction

Visceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. There was no sign of donorderived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function. Beige adipocytes interact continuously with immune cells, and the acquisition of thermogenic features (beiging) requires induction of the anti-inflammatory cytokines interleukin-4 (IL4) by leukocytes in subcutaneous adipose tissue (SAT)[8,9]. The results indicate that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat, and implicate beige fat-stimulated IL4 production by meningeal lymphocytes in communication between SAT and the CNS

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