Sonic hedgehog signaling instigates high-fat diet–induced insulin resistance by targeting PPARγ stability

Abstract

Obesity is a major risk for patients with chronic metabolic disorders including type 2 diabetes. Sonic hedgehog (Shh) is a morphogen that regulates the pancreas and adipose tissue formation during embryonic development. Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear receptor superfamily and one of the most important regulators of insulin action. Here, we evaluated the role and mechanism of Shh signaling in obesity-associated insulin resistance and characterized its effect on PPAR␥. We showed that Shh expression was up-regulated in subcutaneous fat from obese mice. In differentiated 3T3-L1 and primary cultured adipocytes from rats, recombinant Shh protein and SAG (an agonist of Shh signaling) activated an extracellular signal-regulated kinase (ERK)-dependent noncanonical pathway and induced PPAR␥ phosphorylation at serine 112, which decreased PPAR␥ activity. Meanwhile, Shh signaling degraded PPAR␥ protein via binding of PPAR␥ to neural precursor cell-expressed developmentally down-regulated protein 4-1 (NEDD4-1). Furthermore, vismodegib, an inhibitor of Shh signaling, attenuated ERK phosphorylation induced by a high fat diet (HFD) and restored PPAR␥ protein level, thus ameliorating glucose intolerance and insulin resistance in obese mice. Our finding suggests that Shh in subcutaneous fat decreases PPAR␥ activity and stability via activation of an ERK-dependent noncanonical pathway, resulting in impaired insulin action. Inhibition of Shh may serve as a potential therapeutic approach to treat obesity-related diabetes.

Lipid metabolism adaptations are reduced in human compared to murine Schwann cells following injury

“…2 and 4b, c) suggesting reciprocal expression. In adipocytes SHH decreases PPARg activity 62 and a similar mechanism might occur during murine PNI. In human nerves, lack of SHH induction would fail to suppress PPARg and thereby maintain lipogenic gene expression.…”

Interstitial Cell Remodeling Promotes Aberrant Adipogenesis in Dystrophic Muscles

“…Thus, although GDF10 can reduce the replacement of myofibers with adipose tissue, it should be noted that it might also have a negative effect on the muscle function itself. Furthermore, as PPARg is considered a master regulator, its expression is controlled through multiple mechanisms, including hedgehog, Wnt/b-catenin, and bone morphogenesis protein (BMP)mediated signaling pathways (Du et al, 2010;Platko et al, 2019;Yao et al, 2019). From our data, it is likely that GDF10 acts through one of these mechanisms, as the overexpression of GDF10 does not fully block adipogenesis.…”

Peroxisome Proliferator Activated Receptor Gamma Sensitizes Non-small Cell Lung Carcinoma to Gamma Irradiation Induced Apoptosis

“…The activation of Hedgehog signaling leads to the proliferation of cells through MAPK signaling pathway (Liu et al, 2018). There are studies suggesting that sonic Hedgehog signaling (SHH) leads to the phosphorylation of PPARG at ser112 and thereby lead to its degradation (Yao et al, 2019). Due to this, inhibitors of SHH signaling including Vismodegib have been used along with PPARG agonist rosiglitazone in patient samples for treating solid tumors (LoRusso et al, 2013).…”