Adiponectin and PPAR: a setup for intricate crosstalk between obesity and non-alcoholic fatty liver disease

Ishtiaq, Syeda Momna; Rashid, Haroon; Hussain, Zulfia; Arshad, Muhammad Imran; Khan, Junaid

doi:10.1007/s11154-019-09510-2

Cited by 50 publications

(38 citation statements)

References 87 publications

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“…Thiazolidinediones increase the serum adiponectin level under the control of peroxisome proliferator-activated receptor gamma. Increased adiponectin, through AdipoR1 and AdipoR2, activates the adenosine monophosphate-activated protein kinase pathway, thereby inhibiting lipogenesis and accelerating fatty acid oxidation in the liver 25 . Taking the present data and previous study together 26 , we concluded that the beneficial effects by thiazolidinedione on NAFLD were mainly through the increased adiponectin level; that is, the improvement of adipose tissue quality.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the effects of three kinds of glucose‐lowering drugs on non‐alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open‐label, three‐arm, active control study

Kinoshita

Shimoda

Nakashima

et al. 2020

J of Diabetes Invest

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Aims/Introduction Non‐alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus. Materials and Methods We carried out a prospective clinical trial (a randomized and open‐label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin ( n = 32), pioglitazone ( n = 33) or glimepiride ( n = 33) group, and the patients took these drugs for 28 weeks. The primary end‐point was the change of the liver‐to‐spleen ratio on abdominal computed tomography. Results There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver‐to‐spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver‐to‐spleen ratio were comparable. Conclusions The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.

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Section: Discussionmentioning

confidence: 99%

Comparison of the effects of three kinds of glucose‐lowering drugs on non‐alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open‐label, three‐arm, active control study

Kinoshita

Shimoda

Nakashima

et al. 2020

J of Diabetes Invest

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show abstract

“…(29,30) Adiponectin stimulates fatty acid oxidation, decreases inflammation and fibrosis, and improves insulin sensitivity. (31)(32)(33) Adiponectin levels progressively decrease from NAFL to NASH and have been used to develop noninvasive diagnostic tools for staging NAFLD. (34,35) Treatment with CHS-131 increased the circulating levels of adiponectin ~2.4fold, which is similar to the increase observed in humans treated with pioglitazone.…”

Section: Discussionmentioning

confidence: 99%

The Selective Peroxisome Proliferator‐Activated Receptor Gamma Modulator CHS‐131 Improves Liver Histopathology and Metabolism in a Mouse Model of Obesity and Nonalcoholic Steatohepatitis

et al. 2020

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CHS‐131 is a selective peroxisome proliferator‐activated receptor gamma modulator with antidiabetic effects and less fluid retention and weight gain compared to thiazolidinediones in phase II clinical trials. We investigated the effects of CHS‐131 on metabolic parameters and liver histopathology in a diet‐induced obese (DIO) and biopsy‐confirmed mouse model of nonalcoholic steatohepatitis (NASH). Male C57BL/6JRj mice were fed the amylin liver NASH diet (40% fat with trans‐fat, 20% fructose, and 2% cholesterol). After 36 weeks, only animals with biopsy‐confirmed steatosis and fibrosis were included and stratified into treatment groups (n = 12‐13) to receive for the next 12 weeks (1) low‐dose CHS‐131 (10 mg/kg), (2) high‐dose CHS‐131 (30 mg/kg), or (3) vehicle. Metabolic parameters, liver pathology, metabolomics/lipidomics, markers of liver function and liver, and subcutaneous and visceral adipose tissue gene expression profiles were assessed. CHS‐131 did not affect body weight, fat mass, lean mass, water mass, or food intake in DIO‐NASH mice with fibrosis. CHS‐131 improved fasting insulin levels and insulin sensitivity as assessed by the intraperitoneal insulin tolerance test. CHS‐131 improved total plasma cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase and increased plasma adiponectin levels. CHS‐131 (high dose) improved liver histology and markers of hepatic fibrosis. DIO‐NASH mice treated with CHS‐131 demonstrated a hepatic shift to diacylglycerols and triacylglycerols with a lower number of carbons, increased expression of genes stimulating fatty acid oxidation and browning, and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis, and inflammation in adipose tissue. Conclusion: CHS‐131 improves liver histology in a DIO and biopsy‐confirmed mouse model of NASH by altering the hepatic lipidome, reducing insulin resistance, and improving lipid metabolism and inflammation in adipose tissue.

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“…PPARγ activation by FGF21 in adipocytes increases Adipoq mRNA expression and increases the concentration of adiponectin circulating in the blood (Holland et al 2013;Lin et al 2013). Subsequent adiponectin binding to hepatic receptors (AdipoR2) causes PPARα activation in hepatocytes (Yamauchi et al 2007;Ishtiaq et al 2019) that may promote Fgf21 mRNA expression and endocrine secretion of FGF21 (Badman et al 2007;Inagaki et al 2007). This mechanism indicates that autocrine/paracrine signaling by adipocyte FGF21 triggers a feed-forward loop that promotes endocrine FGF21 signaling by the liver (Fig.…”

Section: Cross-talk Between Adipose Tissue and The Livermentioning

confidence: 99%

A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21

et al. 2020

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The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.

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Adiponectin and PPAR: a setup for intricate crosstalk between obesity and non-alcoholic fatty liver disease

Cited by 50 publications

References 87 publications

Comparison of the effects of three kinds of glucose‐lowering drugs on non‐alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open‐label, three‐arm, active control study

Comparison of the effects of three kinds of glucose‐lowering drugs on non‐alcoholic fatty liver disease in patients with type 2 diabetes: A randomized, open‐label, three‐arm, active control study

The Selective Peroxisome Proliferator‐Activated Receptor Gamma Modulator CHS‐131 Improves Liver Histopathology and Metabolism in a Mouse Model of Obesity and Nonalcoholic Steatohepatitis

A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21

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