Liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways

Zhou, Jin-Jian; Poudel, Anil; Welchko, Ryan; Mekala, Naveen Kumar; Chandramani-Shivalingappa, Prashanth; Roșca, Mariana G.; Li, Lixin

doi:10.1016/j.ejphar.2019.172594

Cited by 50 publications

(37 citation statements)

References 55 publications

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“…Interestingly, liraglutide treatment reversed the downregulation of GLP-1R expression in both in vivo and in vitro NAFLD models. Therefore, the systemic metabolic effects of GLP-1RAs might be attributed to a combination of the abovedescribed mechanisms (Zhou et al, 2019;Mantovani et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

Fang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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Liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), has been demonstrated to alleviate non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism has not been fully elucidated. Increasing evidence suggests that autophagy is involved in the pathogenesis of hepatic steatosis. In this study, we examined whether liraglutide could alleviate hepatic steatosis through autophagy-dependent lipid degradation and investigated the underlying mechanisms. Herein, the effects of liraglutide on NAFLD were evaluated in a high-fat diet (HFD)-induced mouse model of NAFLD as well as in mouse primary and HepG2 hepatocytes exposed to palmitic acid (PA). The expression of the GLP-1 receptor (GLP-1R) was measured in vivo and in vitro. Oil red O staining was performed to detect lipid accumulation in hepatocytes. Electron microscopy was used to observe the morphology of autophagic vesicles and autolysosomes. Autophagic flux activity was measured by infecting HepG2 cells with mRFP-GFP-LC3 adenovirus. The roles of GLP-1R and transcription factor EB (TFEB) in autophagy-lysosomal activation were explored using small interfering RNA. Liraglutide treatment alleviated hepatic steatosis in vivo and in vitro. In models of hepatic steatosis, microtubule-associated protein 1B light chain-3-II (LC3-II) and SQSTM1/P62 levels were elevated in parallel to blockade of autophagic flux. Liraglutide treatment restored autophagic activity by improving lysosomal function. Furthermore, treatment with autophagy inhibitor chloroquine weakened liraglutide-induced autophagy activation and lipid degradation. TFEB has been identified as a key regulator of lysosome biogenesis and autophagy. The protein levels of nuclear TFEB and its downstream targets CTSB and LAMP1 were decreased in hepatocytes treated with PA, and these decreases were reversed by liraglutide treatment. Knockdown of TFEB expression compromised the effects of liraglutide on lysosome biogenesis and hepatic lipid accumulation. Mechanistically, GLP-1R expression was decreased in HFD mouse livers as well as PA-stimulated hepatocytes, and liraglutide treatment reversed the downregulation of GLP-1R expression in vivo and in vitro. Moreover, GLP-1R inhibition could mimic the effect of the TFEB downregulation-mediated decrease in lysosome biogenesis. Thus, our findings suggest that liraglutide attenuated hepatic steatosis via restoring autophagic flux, specifically the GLP-1R-TFEB-mediated autophagy-lysosomal pathway.

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Section: Discussionmentioning

confidence: 99%

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

Fang

Zhu

et al. 2020

Front. Cell Dev. Biol.

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“…Liraglutide significantly reduced both circulating and hepatic levels of IL-6 in diabetic mice 93 as well as IL-6 expression in the hippocampus, suggesting protection against neuroinflammation. 94 In T2DM patients, a recent meta-analysis of 13 randomized controlled trials ( n = 1187; follow-up ranged from 8 to 24 weeks), found that IL-6 concentrations were significantly lower [mean difference (MD): -3.90; 95%CI: −5.03 to −2.76, p < 0.00001] in the liraglutide group (1.2 mg/day) compared with the controls in those with stage 3 diabetic nephropathy.…”

Section: Introductionmentioning

confidence: 92%

Anti-inflammatory properties of antidiabetic drugs: A “promised land” in the COVID-19 era?

Katsiki

Ferrannini

2020

Journal of Diabetes and its Complications

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Inflammation is implicated in the development and severity of the coronavirus disease 2019 (COVID-19), as well as in the pathophysiology of diabetes. Diabetes, especially when uncontrolled, is also recognized as an important risk factor for COVID-19 morbidity and mortality. Furthermore, certain inflammatory markers [ i.e. C-reactive protein (CRP), interleukin-6 (IL-6) and ferritin] were reported as strong predictors of worse outcomes in COVID-19 positive patients. The same biomarkers have been associated with poor glycemic control. Therefore, achieving euglycemia in patients with diabetes is even more important in the era of the COVID-19 pandemic. Based on the above, it is clinically interesting to elucidate whether antidiabetic drugs may reduce inflammation, thus possibly minimizing the risk for COVID-19 development and severity. The present narrative review discusses the potential anti-inflammatory properties of certain antidiabetic drugs ( i.e. metformin, pioglitazone, sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin, liraglutide, dulaglutide, exenatide, lixisenatide, semaglutide, empagliflozin, dapagliflozin, canagliflozin), with a focus on CRP, IL-6 and ferritin.

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“…[ 45,46 ] Notably, several recent studies provide evidences for UCP‐1 induction in skeletal muscle by stimuli like agonist or natural extract, in supporting of the contribution of UCP‐1 to energy dissipation in skeletal muscle. [ 47–52 ] Both brown adipocytes and skeletal myoblasts origin from Myf5‐positive precursors, to some extent, share overlapping transcriptional program. Brown adipocyte progenitors or common progenitors shared by brown adipocytes and myocytes reside in skeletal muscle, which can differentiate into UCP1‐positive cells under certain circumstances.…”

Section: Discussionmentioning

confidence: 99%

Oral Spermidine Targets Brown Fat and Skeletal Muscle to Mitigate Diet‐Induced Obesity and Metabolic Disorders

Wang

Yin

Zhou

et al. 2021

Molecular Nutrition Food Res

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Introduction Obesity causes many life‐threatening diseases. It is important to develop effective approaches for obesity treatment. Oral supplementation with spermidine retards age‐related processes, but its influences on obesity and various metabolic tissues remain largely unknow. This study aims to investigate the effects of oral spermidine on brown adipose tissue (BAT) and skeletal muscle as well as its roles in counteracting obesity and metabolic disorders. Methods and Results Spermidine is orally administrated into high‐fat diet (HFD)‐fed mice. The weight gain, insulin resistance, and hepatic steatosis are attenuated by oral spermidine in HFD‐fed mice, accompanied by an alleviation of white adipose tissue inflammation. Oral spermidine promotes BAT activation and metabolic adaptation of skeletal muscle in HFD‐fed mice, evidenced by UCP‐1 induction and CREB activation in both tissues. Notably, oral spermidine upregulates tyrosine hydroxylase in hypothalamus of HFD‐fed mice; spermidine treatment increases tyrosine hydroxylase expression and norepinephrine production in neurocytes, which leads to CREB activation and UCP‐1 induction in brown adipocytes and myotubes. Spermidine also directly promotes UCP‐1 and PGC‐1α expression in brown adipocytes and myotubes. Conclusion Spermidine serves as an oral supplement to attenuate obesity and metabolic disorders through hypothalamus‐dependent or ‐independent BAT activation and skeletal muscle adaptation.

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Liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways

Cited by 50 publications

References 55 publications

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

Liraglutide Alleviates Hepatic Steatosis by Activating the TFEB-Regulated Autophagy-Lysosomal Pathway

Anti-inflammatory properties of antidiabetic drugs: A “promised land” in the COVID-19 era?

Oral Spermidine Targets Brown Fat and Skeletal Muscle to Mitigate Diet‐Induced Obesity and Metabolic Disorders

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