PPARα suppresses insulin secretion and induces UCP2 in insulinoma cells

Tordjman, Karen; Standley, Kara N.; Bernal‐Mizrachi, Carlos; Leone, Teresa C.; Coleman, Trey; Kelly, Daniel P.; Semenkovich, Clay F.

doi:10.1016/s0022-2275(20)30468-5

Cited by 76 publications

(6 citation statements)

References 47 publications

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“…Pancreas-specific Sirt1-deficient mice (Pdx1-Cre; Sirt1 flox/flox ) present with glucose intolerance and impaired GSIS of β-cells (Luu et al, 2013;Wang R.H. et al, 2013;Pinho et al, 2015). SIRT1-mediated deacetylation and subsequent repression of Ucp2 normally activates GSIS (Tordjman et al, 2002;Bordone et al, 2006;Chan and Kashemsant, 2006;Brun et al, 2015), however, the absence or reduction of pancreatic SIRT1 results in increased acetylation and expression of Ucp2 (Bordone et al, 2006) and other downstream target genes, such as Pgc-1α, Pparγ (Luu et al, 2013), and Pparα (Maiztegui et al, 2018), leading to decreased GSIS. Similarly, upon high glucose exposure (Brun et al, 2015), or the addition of sucrose (10%) to a normal diet (Maiztegui et al, 2018), pancreatic SIRT1 expression is decreased, while Ucp2 and Pparα expression is increased in human and rodent islets, leading to reductions in insulin content and GSIS of β-cells (Brun et al, 2015;Maiztegui et al, 2018).…”

Section: Histone Acetylation/deacetylationmentioning

confidence: 99%

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

et al. 2020

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The global prevalence of metabolic disorders, such as obesity, diabetes and fatty liver disease, is dramatically increasing. Both genetic and environmental factors are wellknown contributors to the development of these diseases and therefore, the study of epigenetics can provide additional mechanistic insight. Dietary interventions, including caloric restriction, intermittent fasting or time-restricted feeding, have shown promising improvements in patients' overall metabolic profiles (i.e., reduced body weight, improved glucose homeostasis), and an increasing number of studies have associated these beneficial effects with epigenetic alterations. In this article, we review epigenetic changes involved in both metabolic diseases and dietary interventions in primary metabolic tissues (i.e., adipose, liver, and pancreas) in hopes of elucidating potential biomarkers and therapeutic targets for disease prevention and treatment.

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Section: Histone Acetylation/deacetylationmentioning

confidence: 99%

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

et al. 2020

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“…AdPPARα (containing the mouse Ppara cDNA) was generated, and administered as described (Tordjman et al 2002;Bernal-Mizrachi et. al 2003).…”

Section: Adenovirus Treatmentmentioning

confidence: 99%

An Afferent Vagal Nerve Pathway Links Hepatic PPARα Activation to Glucocorticoid-Induced Insulin Resistance and Hypertension

Bernal‐Mizrachi

Liu

et al. 2007

Cell Metabolism

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Glucocorticoid excess causes insulin resistance and hypertension. Hepatic expression of PPARalpha (Ppara) is required for glucocorticoid-induced insulin resistance. Here we demonstrate that afferent fibers of the vagus nerve interface with hepatic Ppara expression to disrupt blood pressure and glucose homeostasis in response to glucocorticoids. Selective hepatic vagotomy decreased hyperglycemia, hyperinsulinemia, hepatic insulin resistance, Ppara expression, and phosphoenolpyruvate carboxykinase (PEPCK) enzyme activity in dexamethasone-treated Ppara(+/+) mice. Selective vagotomy also decreased blood pressure, adrenergic tone, renin activity, and urinary sodium retention in these mice. Hepatic reconstitution of Ppara in nondiabetic, normotensive dexamethasone-treated PPARalpha null mice increased glucose, insulin, hepatic PEPCK enzyme activity, blood pressure, and renin activity in sham-operated animals but not hepatic-vagotomized animals. Disruption of vagal afferent fibers by chemical or surgical means prevented glucocorticoid-induced metabolic derangements. We conclude that a dynamic interaction between hepatic Ppara expression and a vagal afferent pathway is essential for glucocorticoid induction of diabetes and hypertension.

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“…There is less consensus on whether lipotoxicity is an independent driver of β-cell dysfunction in T2D. Much of the supportive evidence is derived from in vitro islet studies, which have linked supra-physiological doses of specific fatty acids to defects in β-cell function [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

Valdez

Palavicini

Bakewell

et al. 2022

Preprint

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Insulin resistance is a hallmark feature of Type 2 Diabetes (T2D), but the progression of the disease is closely linked to a deterioration in β-cell mass and function. While the precise mechanisms of β-cell failure are unclear, chronic hyperglycemia (glucotoxicity) and dyslipidemia (lipotoxicity) are considered contributing factors; however, the relative importance of these insults on β-cell function remains controversial. To examine this, we dissociated glucotoxicity from lipotoxicity using a high-fat diet (HFD)-fed mouse model of T2D and the glucose-lowering SGLT2 inhibitor, canagliflozin (CANA). As expected, HFD-feeding impaired glucose tolerance and isolated islet function. However, despite improvements in glucose tolerance and indices of β-cell insulin secretory function in vivo, CANA failed to restore isolated β-cell function. Shotgun lipidomics analysis of isolated islets revealed that HFD-feeding induced glycerophospholipid remodeling with a persistent increase in arachidonic acid (20:4)-enriched molecular species. Further analysis revealed that lysophosphatidylcholine (LPC) was the predominant lipid class elevated in HFD islets following correction of glucotoxicity with CANA. In follow-up experiments, LPC stimulations acutely and dose-dependently impaired glucose-stimulated insulin secretion (GSIS) in isolated wild-type islets, mechanistically linking this lipid class to β-cell dysfunction. Our findings indicate that persistent inflammatory lipotoxicity impedes β-cell function in diet-induced obese (DIO) rodents even after normalization of hyperglycemia. If replicated in humans, these data suggest that interventions targeting lipotoxicity may be beneficial for the long-term protection of pancreatic β-cell function in T2D.

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PPARα suppresses insulin secretion and induces UCP2 in insulinoma cells

Cited by 76 publications

References 47 publications

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

An Afferent Vagal Nerve Pathway Links Hepatic PPARα Activation to Glucocorticoid-Induced Insulin Resistance and Hypertension

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

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