The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle

Guzzardi, Maria Angela; Hodson, Leanne; Guiducci, Letizia; Rosa, Federica La; Salvadori, Piero A.; Burchielli, Silvia; Iozzo, Patricia

doi:10.1016/j.numecd.2017.08.002

Cited by 7 publications

(6 citation statements)

References 26 publications

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“…Glucose contributes to the synthesis of fatty acids esterified into TGs that are simultaneously hydrolyzed to drive brown adipocyte thermogenesis ( 86 ). Glucose availability increases insulin-mediated TG synthesis and fatty acid storage in adipocytes in vitro ( 87–89 ), but also in vivo ( 90 ). Carbohydrate-response element-binding protein (ChERBP), which is activated by cold exposure and by increased glucose availability ( 91 ), and which controls the genes that drive de novo lipogenesis, plays an important role in BAT TG accumulation in mice ( 92 ).…”

Section: Cellular Biology Of Brown Adipose Tissuementioning

confidence: 99%

Brown Adipose Tissue—A Translational Perspective

et al. 2022

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Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography (PET) with 18F-fluorodeoxiglucose ( 18FDG), which can be dissociated from BAT thermogenic activity, as for example in insulin resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride (TG) lipolysis. This lipolytic BAT response is intertwined with that of white adipose and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body’s thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in white adipose and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases.

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Section: Cellular Biology Of Brown Adipose Tissuementioning

confidence: 99%

Brown Adipose Tissue—A Translational Perspective

et al. 2022

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“…Plasma NEFA, as the major source of fatty acids for TG synthesis, causes abnormal lipid accumulation, which leads to the development of NAFLD [32,33]. In the present study, the content of TG was measured with an enzyme-linked immunosorbent assay, which indicated that NEFA stimulated TG synthesis and secretion or insulin resistance, resulting in the accumulation of TG.…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 64%

NEFA-Sensitive Orai1 Expression in Regulation of De Novo Lipogenesis

Zhang¹,

Yang²,

Zou³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Non-esterified fatty acids (NEFAs) are important inducers of inflammatory responses and hepatic lipid accumulation, which lead to non-alcoholic fatty liver disease (NAFLD). High plasma NEFA is found in NAFLD patients, and associated with metabolic syndrome and type-2 diabetes. NFκB is known to upregulate Orai1, the Ca²⁺ channel responsible for store-operated Ca²⁺ entry. The present study explored the role of NEFA-sensitive NFκB-dependent Orai1 expression in the regulation of lipid synthesis. Methods: BRL-3A rat liver hepatocyte lines were studied in the absence and presence of NEFA. Transcript and protein expression levels of factors involved in lipid synthesis were quantified by quantitative polymerase chain reaction (qPCR) and western blot analyses. Fatty acids were measured by immunofluorescence. Results: NEFA significantly increased, as indicated by the expression of sterol regulatory element-binding protein 1 (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase α (ACC1), Orai1, and NFκB p65 by qPCR and western blot analyses. These effects were reversed by the Orai1 inhibitor, 2-aminoethoxydiphenyl borate, and the NFκB inhibitor, wogonin. Furthermore, SREBP-1c, FAS, ACC1, and Orai1 were significantly decreased by Orai1 silencing. Conclusions: Taken together, these results demonstrated that NEFA-sensitive NFκB-dependent Orai1 expression regulates de novo lipogenesis.

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“…Crosstalk between adipose tissue and the liver is a key mechanism underlying MASLD development and progression. The major source of non-esterified fatty acids (NEFAs) is peripheral fat stored in adipose tissue [69]. After release from fat depots, NEFAs flow to the liver and accumulate in the form of triglycerides.…”

Section: Insulin Resistance-from Adipose Tissue To the Livermentioning

confidence: 99%

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

Vesković,

Šutulović,

Hrnčić

et al. 2023

CIMB

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The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

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The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle

Cited by 7 publications

References 26 publications

Brown Adipose Tissue—A Translational Perspective

Brown Adipose Tissue—A Translational Perspective

NEFA-Sensitive Orai1 Expression in Regulation of De Novo Lipogenesis

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease—The Transition from an Adipocentric to Liver-Centric Approach

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