AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity

Abstract

Fibrosis is emerging as a hallmark of metabolically dysregulated white adipose tissue (WAT) in obesity. Although adipose tissue fibrosis impairs adipocyte plasticity, little is known about how aberrant extracellular matrix (ECM) remodeling of WAT is initiated during the development of obesity. Here we show that treatment with the antidiabetic drug metformin inhibits excessive ECM deposition in WAT of ob/ob mice and mice with diet-induced obesity, as evidenced by decreased collagen deposition surrounding adipocytes and expression of fibrotic genes including the collagen cross-linking regulator LOX. Inhibition of interstitial fibrosis by metformin is likely attributable to the activation of AMPK and the suppression of transforming growth factor-β1 (TGF-β1)/Smad3 signaling, leading to enhanced systemic insulin sensitivity. The ability of metformin to repress TGF-β1-induced fibrogenesis is abolished by the dominant negative AMPK in primary cells from the stromal vascular fraction. TGF-β1-induced insulin resistance is suppressed by AMPK agonists and the constitutively active AMPK in 3T3L1 adipocytes. In omental fat depots of obese humans, interstitial fibrosis is also associated with AMPK inactivation, TGF-β1/Smad3 induction, aberrant ECM production, myofibroblast activation, and adipocyte apoptosis. Collectively, integrated AMPK activation and TGF-β1/Smad3 inhibition may provide a potential therapeutic approach to maintain ECM flexibility and combat chronically uncontrolled adipose tissue expansion in obesity.

The neurobiology of the Prader-Willi phenotype of fragile X syndrome

“…Metformin is known to decrease body mass index (BMI) and to prevent cognitive deficits in individuals with diabetes (55)(56)(57)(58)(59). Metformin decreases protein synthesis and insulin-signaling via the AMPK/Akt/ mTOR pathway, it also inhibits the lipid and sterol biosynthetic pathways (60)(61)(62)(63) (Figure 3). Therefore, metformin in FXS may decrease insulin-signaling and restore the circadian output pathway and in turn have positive effects on memory and sleep.…”

Contributions of innate type 2 inflammation to adipose function

“…There has been some progress made in understanding how drugs can modulate inflammation to improve obesity and/or it's comorbidities, such as T2D and insulin resistance. The most commonly prescribed drug for T2D patients, metformin, improves insulin sensitivity and reduces hepatic glucose production, and has also been shown to reduce inflammatory markers [61,62]. Yet it is unclear whether the reduced inflammation was required for the metabolic benefits seen in humans, and furthermore if A recent study showed that the anti-inflammatory drug Amlexanox, previously used to treat allergic conditions, reduced HbA1c in obese and T2D patients [67].…”

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

“…Another study [31] demonstrated that metformin may protect against cisplatin-induced tubular cell apoptosis and AKI by stimulating AMPKα activation and autophagy induction in the tubular cells. Study by Ting Luo et al [22] also found that metformin repressed the TGF-β1-induced fibrogenic response via AMPK in vitro, which might account for the beneficial influences of metformin on fat fibrosis in obesity in vivo. The results of this study indicated that by activating AMPK phosphorylation, metformin potently inhibited PSCs proliferation and ECM production.…”

“…Previous studies have shown that metformin has antifibrotic effects beyond its antihyperglycaemic and antitumour action. For example, Ting L et al [22] have shown that treatment with metformin inhibited excessive ECM deposition in white adipose tissue of obese mice. Shen Y et al [23] have found that metformin inhibited the activation of ERK signalling and attenuated the production of ECM proteins and collagen deposition in the obstructed kidneys.…”