Obesity is frequently concomitant with chronic adipose inflammation, although its role in the pathophysiology of obesity remains inconclusive. We previously described that constitutively suppressing adipose inflammation indeed impairs adipose development and leads to profound systemic metabolic disturbances. RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TNFα and IL1β. To avoid developmental issues, we generated a tet-responsive promoter-driven RIDα/β (“TRE-RID”) mouse and crossed it to an adiponectinP-rtTA mouse to achieve doxycycline(dox)-inducible, adipocyte-specific expression of this transgene (referred to as fatRID mice).

We induced RIDα/β expression with dox-chow diet at 8-weeks of age. Upon induction, RIDα/β is specifically expressed in adipocytes, but not in the liver. LPS-stimulated inflammatory markers, such as TNFα, IL1β and Saa3 are significantly decreased in transgenic mice. Under dox-chow fed conditions, fatRID mice display higher levels of glucose and insulin upon refeeding. FatRID mice exhibit glucose intolerance and insulin resistance. Under obesogenic condition with high-fat-diet (HFD, supplement with dox) feeding, fatRID mice gain less weight, but also display insulin resistance. Moreover, to precondition the mice with inflammation and obesity, mice were pre-fed with HFD without dox for 30 days, and then switched to dox-containing HFD. Under these conditions, fatRID mice exhibit similar body weights, but still display glucose intolerance, insulin resistance, massive fatty liver and reduced adiponectin levels. These metabolic impairments were seen despite the fact that inflammatory pathways (including TNFα and IL1β) are effectively reduced.

Combined, suppressing adipose inflammation under either normal or obese conditions promotes insulin resistance, despite beneficial (or minimally no negative) effects on body weight.


Q. Zhu: None. P.E. Scherer: None.


National Institutes of Health

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