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.
RIDα/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 (RID ad and RID mac mice, respectively).
RIDα/β induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, RID ad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RID ad 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 RID ad 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, RID mac 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.
Suppression of adipocyte inflammation promotes insulin resistance under both normal and obesogenic conditions.
Suppression of adipocyte inflammation with pre-existing obesity further aggravates insulin resistance.
Suppression of macrophage inflammation has little effect on obesity-induced insulin resistance.
Adipocyte inflammation may therefore be required to maintain normal adipose tissue function.