Abstract
ObjectiveObesity-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. MethodsRIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNFα, and IL1β signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RIDα/β-transgenic mice (RIDad and RIDmac mice, respectively). ResultsRIDα/β induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, 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 RIDα/β 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 TNFα and IL1β). 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. RIDα/β expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization. ConclusionOur 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.
Highlights
Obesity-associated insulin resistance is a major risk factor for multiple comorbidities, including type 2 diabetes, cardiovascular diseases, and several types of cancers [1,2]
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
Adipose tissue inflammation is subject to normal physiological variations over a significant range
Summary
Obesity-associated insulin resistance is a major risk factor for multiple comorbidities, including type 2 diabetes, cardiovascular diseases, and several types of cancers [1,2]. Interventions in clinical trials, such as anti-TNFa antibodies, statins, glucocorticoids, and IL1b receptor antagonists, fail to improve but frequently even worsen insulin sensitivity. They may lower hyperglycemia independent of insulin sensitivity [9e13]. Approximately 20e40% of all cells consist of adipocytes, while the rest are composed of preadipocytes, endothelial cells, and many immune cells taking part in both the innate and adaptive immune systems [14]. Among these cells, macrophages are a very prominent immune cell type in adipose tissue. While they represent less than 10% of all cells in the lean state, they
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