Suppressing adipocyte inflammation promotes insulin resistance in mice

Abstract

Objective: Obesity-induced insulin resistance is closely associated with chronic subclinical inflammation in white adipose tissue. However, the mechanistic involvement of adipocyte-derived inflammation under these disease conditions remains unclear. Our aim was to investigate the relative inflammation-related contributions of adipocytes and macrophages to insulin sensitivity. Methods: RID alpha/beta is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNF alpha, and IL1 beta signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RID alpha/beta-transgenic mice (RIDad and RIDmac mice, respectively). Results: RID alpha/beta induction significantly reduced LPS-stimulated inflammatory markers, such as Tnt, fl1b, and Saa3 in adipose tissues. Sur-prisingly, RIDad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RIDad mice displayed further insulin resistance under obesogenic (high-fat diet, HFD) conditions despite reduced weight gain. In addition, under pre-existing obese and inflamed conditions on an HFD, subsequent induction of RID alpha/beta in RIDad mice reduced body weight gain, further exacerbating glucose tolerance, enhancing insulin resistance and fatty liver, and reducing adiponectin levels. This occurred despite effective suppression of the inflammatory pathways (including TNF alpha and IL1 beta). In contrast, RIDmac mice, upon HFD feeding, displayed similar weight gain, comparable adiponectin levels, and insulin sensitivity, suggesting that the inflammatory properties of macrophages did not exert a negative impact on metabolic readouts. RIDa/b expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization. Conclusion: Our novel findings further corroborate our previous observations suggesting that suppressing adipocyte inflammation impairs adipose tissue function and promotes insulin resistance, despite beneficial effects on weight gain. (C) 2020 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).