Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3

Abstract

Highlights d Blocking PPARg S273 phosphorylation protects mice from insulin resistance in obesity d These mice do not show the side effects associated with TZD-based PPARg agonism d These mice have reduced expression of Gdf3 mainly in macrophages d Gdf3 is sufficient to cause impaired glucose homeostasis in vivo and in vitro

Association Between Systemic Immune-Inflammation Index and Diabetic Depression

“…Preclinical and clinical studies have shown a causal link between sterile low-grade inflammation and depression in patients with DM. [8][9][10][11][12] Study showed that a high-fat diet leads to an increase in inflammatory cytokine levels and to anxiety and depressive behaviors. 13,14 Antidepressant administration decreased the inflammatory cytokine levels and reversed the behavioral deficits caused by a high-fat diet.…”

Chronic tissue inflammation and metabolic disease

“…An additional key early study showed increased TNFα levels in the adipose tissue of obese mice and showed that neutralization of TNFα ameliorates insulin resistance (Hotamisligil et al 1993). Numerous studies have identified various molecules within the inflammatory signaling cascade that can impair insulin signaling, such as JNK, IKKβ, and various cytokines (Xia et al 2015;Goldfine and Shoelson 2017;Hotamisligil 2017;Zhao et al 2018;Donath et al 2019;Hall et al 2020). Many reports have identified a mechanistic link between chronic inflammation and insulin resistance in rodent studies by use of various genetic gain-and loss-of-function studies (Lee et al 2018).…”

Hexane Extract of Chloranthus japonicus Increases Adipocyte Differentiation by Acting on Wnt/β-Catenin Signaling Pathway

“…Although TZDs are used in the diabetes, adverse effects have limited their clinical use [ 9 , 10 ]. However, studies on Pparγ expression and its modification have brought attention back to Pparγ [ 11 , 12 , 13 ]. The induction of Pparγ expression by the small molecule harmine improves insulin sensitivity with little effect on weight gain, suggesting that inducing Pparγ expression can be used against obesity related insulin dysfunctions [ 14 ].…”

“…The induction of Pparγ expression by the small molecule harmine improves insulin sensitivity with little effect on weight gain, suggesting that inducing Pparγ expression can be used against obesity related insulin dysfunctions [ 14 ]. Phosphorylation at S273 of Pparγ is positively associated with obesity in rodents [ 13 ]. Furthermore, inhibition of S273 Pparγ phosphorylation ameliorates insulin activity without effects on weight gain and fluid retention [ 13 ].…”

“…Phosphorylation at S273 of Pparγ is positively associated with obesity in rodents [ 13 ]. Furthermore, inhibition of S273 Pparγ phosphorylation ameliorates insulin activity without effects on weight gain and fluid retention [ 13 ]. Therefore, the modulation of Pparγ activity and expression can provide alternative therapeutic strategies against insulin resistance and diabetes.…”