Glucagon regulates lipolysis and fatty acid oxidation through inositol triphosphate receptor 1 in the liver

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Abstract

Glucagon promotes hepatic glucose production, lipolysis and amino acid catabolism. Inhibition of glucagon activity, or glucagon resistance, not only lowers blood glucose levels, but also induces non‐alcoholic fatty liver disease and hyperaminoacidemia.

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Regulation of lipolysis in adipocytes.

Robin Duncan, Maryam Ahmadian, Kathy Jaworski … (2007)

Lipolysis of white adipose tissue triacylglycerol stores results in the liberation of glycerol and nonesterified fatty acids that are released into the vasculature for use by other organs as energy substrates. In response to changes in nutritional state, lipolysis rates are precisely regulated through hormonal and biochemical signals. These signals modulate the activity of lipolytic enzymes and accessory proteins, allowing for maximal responsiveness of adipose tissue to changes in energy requirements and availability. Recently, a number of novel adipocyte triacylglyceride lipases have been identified, including desnutrin/ATGL, greatly expanding our understanding of adipocyte lipolysis. We have also begun to better appreciate the role of a number of nonenzymatic proteins that are critical to triacylglyceride breakdown. This review provides an overview of key mediators of lipolysis and the regulation of this process by changes in nutritional status and nutrient intakes.

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Glucagon stimulates gluconeogenesis by InsP 3 R-I mediated hepatic lipolysis

Rachel J Perry, Dongyan Zhang, Mateus T Guerra … (2020)

While it is well-established that alterations in the portal vein insulin/glucagon ratio play a major role in causing dysregulated hepatic glucose metabolism in type 2 diabetes (T2D) 1–3 , the mechanisms by which glucagon alters hepatic glucose production and mitochondrial oxidation remain poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing hepatic adipose triglyceride lipase activity, intrahepatic lipolysis, hepatic acetyl-CoA content, and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation, mediated by stimulation of the inositol triphosphate receptor-1 (InsP3R-I). Chronic physiological increases in plasma glucagon concentrations increased mitochondrial hepatic fat oxidation and reversed diet-induced hepatic steatosis and insulin resistance in rats and mice; however, the effect of chronic glucagon treatment to reverse hepatic steatosis and glucose intolerance was abrogated in InsP3R-I knockout mice. These results provide new insights into glucagon biology and suggest that InsP3R-I may be a novel therapeutic target to reverse nonalcoholic fatty liver disease and T2D.

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Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones.

Benjamin Renquist, Caroline Geisler (2017)

Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake,de novolipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepaticde novofatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Author and article information

Contributors

Yoshitaka Hayashi:

ORCID: https://orcid.org/0000-0002-7557-4303

hayashiy@riem.nagoya-u.ac.jp

Journal

Journal ID (nlm-ta): J Diabetes Investig

Journal ID (iso-abbrev): J Diabetes Investig

Journal ID (doi): 10.1111/(ISSN)2040-1124

Journal ID (publisher-id): JDI

Title: Journal of Diabetes Investigation

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 2040-1116

ISSN (Electronic): 2040-1124

Publication date (Electronic): 26 July 2020

Publication date (Print): January 2021

Volume: 12

Issue: 1 ( doiID: 10.1111/jdi.v12.1 )

Pages: 32-34

Affiliations

[ ¹ ] Department of Endocrinology Division of Stress Adaptation and Protection Research Institute of Environmental Medicine Nagoya University Nagoya Japan

Author notes

[*] [* ] Corresponding author. Yoshitaka Hayashi

Tel: +81-52-789-5780

Fax: +81-52-789-5003

E-mail address: hayashiy@ 123456riem.nagoya-u.ac.jp

Author information

Yoshitaka Hayashi https://orcid.org/0000-0002-7557-4303

Article

Publisher ID: JDI13315

DOI: 10.1111/jdi.13315

PMC ID: 7779274

PubMed ID: 32506830

SO-VID: e819d6cc-eea6-47cd-8d3a-9e36be072558

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date received : 26 May 2020

Date revision received : 28 May 2020

Date accepted : 01 June 2020

Page count

Figures: 3, Tables: 0, Pages: 3, Words: 1461

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source-schema-version-number 2.0

cover-date January 2021

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:03.01.2021

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Glucagon regulates lipolysis and fatty acid oxidation through inositol triphosphate receptor 1 in the liver

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Most cited references 5

Regulation of lipolysis in adipocytes.

Glucagon stimulates gluconeogenesis by InsP 3 R-I mediated hepatic lipolysis

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones.

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Cited by 8

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