Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice

Lee, Aejin; Sun, Yuan; Lin, Tzu‐Jung; Song, No-Joon; Mason, McKensie L.; Leung, Jacob H.; Kowdley, Devan; Wall, Jennifer L.; Brunetti, A.; Fitzgerald, Julie; Baer, Lisa A.; Stanford, Kristin I.; Ortega‐Anaya, Joana; Gomes-Dias, Laisa; Needleman, Bradley; Noria, Sabrena; Weil, Zachary M.; Blakeslee, Joshua J.; Jiménez-Flores, Rafael; Parquette, Jon R.; Ziouzenkova, Ouliana

doi:10.1016/j.biomaterials.2020.119839

Cited by 7 publications

(19 citation statements)

References 78 publications

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“…Metabolic associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease (NAFLD), inflicts a heavy health burden worldwide ( Eslam et al, 2020 ). In absence of alcohol abuse, it encompasses a spectrum of liver disorders from simple steatosis to steatohepatitis, the latter of which can lead to progressive liver fibrosis ( Lee et al, 2020 ), cirrhosis, and ultimately hepatocellular carcinoma (HCC) ( Kanwal et al, 2019 ). MAFLD is epidemiologically related to obesity and type 2 diabetes mellitus (T2DM).…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Fang

et al. 2021

Front. Pharmacol.

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Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood.Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels.Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment.Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

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Section: Introductionmentioning

confidence: 99%

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Fang

et al. 2021

Front. Pharmacol.

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“…Body composition was measured in living mice using the Body Composition Analyzer for Live Small Animals (EchoMRI™-100H, Houston, TX, USA) as described [10].…”

Section: Body Composition Analysismentioning

confidence: 99%

“…Murine preadipocytes (3T3-L1 fibroblasts, CL-173 from American Type Culture Collection) were cultured as described [10]. Human stromal vascular fraction (SVF) was isolated from the visceral (omental) fat of obese subjects using type 1 collagenase (17100017, Thermo Fisher Scientific) and cultured as described [27].…”

Section: Adipocyte Culturementioning

confidence: 99%

“…Glucose uptake assay was performed using glucose uptake cell-based assay kit (Cayman Chemical, 600470) described in [10]. 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (FD-Glucose) containing medium with or without inhibitors was added to the plated cells in glucose-free DMEM.…”

Section: Glucose Uptake Assaymentioning

confidence: 99%

“…Long cytosolic domains act predominantly in the brain, where they regulate appetite, energy homeostasis, and crosstalk with the insulin pathway [6]. LepR with short intracellular domains is expressed in peripheral tissues [6], where they regulate glucose uptake in response to leptin or pharmacological ligands [10]. Different roles of leptin and LepR in the context of glucose uptake were highlighted in studies using Lep ob [11] and LepR db mice [12].…”

Section: Introductionmentioning

confidence: 99%

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Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity

Song

Lee

Yasmeen

et al. 2022

Cells

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The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in vivo in Lepob mice by activating LepR under leptin-deficient conditions. Single and long-term treatment with EREG effectively rescued glucose intolerance in comparative insulin and EREG tolerance tests in Lepob mice. The immunoprecipitation study revealed binding between EREG and LepR in adipose tissue of Lepob mice. EREG/LepR regulated glucose uptake without changes in obesity in Lepob mice via mechanisms, including ERK activation and translocation of GLUT4 to the cell surface. EREG-dependent glucose uptake was abolished in Leprdb mice which supports a key role of LepR in this process. In contrast, inhibition of the canonical epidermal growth factor receptor (EGFR) pathway implicated in other EREG responses, increased glucose uptake. Our data provide a basis for understanding glycemic responses of EREG that are dependent on LepR unlike functions mediated by EGFR, including leptin secretion, thermogenesis, pain, growth, and other responses. The computational analysis identified a conserved amino acid sequence, supporting an evolutionary role of EREG as an alternative LepR ligand.

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Insulin Resistance Triggers Atherosclerosis: Caveolin 1 Cooperates with PKCzeta to Block Insulin Signaling in Vascular Endothelial Cells

Tan

Dou

2023

Cardiovasc Drugs Ther

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Objective To date, therapies for endothelial dysfunction have primarily focused on ameliorating identified atherosclerosis (AS) risk factors rather than explicitly addressing endothelium-based mechanism. An in-depth exploration of the pathological mechanisms of endothelial injury was performed herein. Methods Aortic caveolin 1 (Cav1) knockdown was achieved in mice using lentivirus, and AS was induced using a high-fat diet. Mouse body weight, blood glucose, insulin, lipid parameters, aortic plaque, endothelial injury, vascular nitric oxide synthase (eNOS), injury marker, and oxidative stress were examined. The effect of Cav1 knockdown on the content of PKCzeta and PI3K/Akt/eNOS pathway–related protein levels, as well as PKCzeta binding to Akt, was studied. ZIP, a PKCzeta inhibitor, was utilized to treat HUVECs in vitro, and the effect of ZIP on cell viability, inflammatory response, oxidative stress, and Akt activation was evaluated. Results Cav1 knockdown had no significant effect on body weight or blood glucose in mice over an 8-week period, whereas drastically reduced insulin, lipid parameters, endothelial damage, E-selectin, and oxidative stress and elevated eNOS levels. Moreover, Cav1 knockdown triggered decreased PKCzeta enrichment and the activation of the PI3K/Akt/eNOS pathway. PKCzeta has a positive effect on cells without being coupled by Cav1, and ZIP had no marked influence on PKCzeta-Akt binding following Cav1/PKCzeta coupling. Conclusion Cav1/PKCzeta coupling antagonizes the activation of PI3K on Akt, leading to eNOS dysfunction, insulin resistance, and endothelial cell damage.

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Amino acid-based compound activates atypical PKC and leptin receptor pathways to improve glycemia and anxiety like behavior in diabetic mice

Cited by 7 publications

References 78 publications

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Epiregulin as an Alternative Ligand for Leptin Receptor Alleviates Glucose Intolerance without Change in Obesity

Insulin Resistance Triggers Atherosclerosis: Caveolin 1 Cooperates with PKCzeta to Block Insulin Signaling in Vascular Endothelial Cells

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