Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons

Mayer, Christopher; Belsham, Denise D.

doi:10.1016/j.mce.2009.02.031

Cited by 82 publications

(74 citation statements)

References 65 publications

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“…PA is the product of phospholipase D-mediated hydrolysis of membrane phospholipids, and it has been suggested that 1) this PA is essential for activation of mTORC1 signaling (10,11), and 2) that insulin activation of the mTORC1/S6K1 pathway causes serine phosphorylation of IRS-1, thereby inhibiting insulin-mediated activation of PI 3-kinase and Akt (20,32). PA is also synthesized by the GPAT-initiated pathway of TAG synthesis (8).…”

Section: Di16:0-pa Increased In Hepatocytes Overexpressing Gpat4 and mentioning

confidence: 99%

Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

Zhang

Cooper

Grevengoed

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Coleman RA. Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor. Am J Physiol Endocrinol Metab 307: E305-E315, 2014. First published June 17, 2014 doi:10.1152/ajpendo.00034.2014.-Glycerol-3-phosphate acyltransferase (GPAT) activity is highly induced in obese individuals with insulin resistance, suggesting a correlation between GPAT function, triacylglycerol accumulation, and insulin resistance. We asked whether microsomal GPAT4, an isoform regulated by insulin, might contribute to the development of hepatic insulin resistance. Compared with control mice fed a high fat diet, Gpat4 Ϫ/Ϫ mice were more glucose tolerant and were protected from insulin resistance. Overexpression of GPAT4 in mouse hepatocytes impaired insulin-suppressed gluconeogenesis and insulin-stimulated glycogen synthesis. Impaired glucose homeostasis was coupled to inhibited insulin-stimulated phosphorylation of Akt(Ser 473 ) and Akt(Thr 308 ). GPAT4 overexpression inhibited rictor's association with the mammalian target of rapamycin (mTOR), and mTOR complex 2 (mTORC2) activity. Compared with overexpressed GPAT3 in mouse hepatocytes, GPAT4 overexpression increased phosphatidic acid (PA), especially di16:0-PA. Conversely, in Gpat4 Ϫ/Ϫ hepatocytes, both mTOR/rictor association and mTORC2 activity increased, and the content of PA in Gpat4 Ϫ/Ϫ hepatocytes was lower than in controls, with the greatest decrease in 16:0-PA species. Compared with controls, liver and skeletal muscle from Gpat4 Ϫ/Ϫ -deficient mice fed a high-fat diet were more insulin sensitive and had a lower hepatic content of di16:0-PA. Taken together, these data demonstrate that a GPAT4-derived lipid signal, likely di16:0-PA, impairs insulin signaling in mouse liver and contributes to hepatic insulin resistance. lipid metabolism; phosphatidic acid; glycerolipids; diabetes; insulin signaling; mammalian target of rapamycin complex 2 THE METABOLIC SYNDROME is a cluster of derangements that includes central obesity, glucose intolerance, dyslipidemia, hypertension, and insulin resistance (16). Insulin resistance is not only a feature of the metabolic syndrome but has also been proposed to be a unifying condition that underlies the pathophysiology of the other metabolic syndrome elements (25).Excessive triacylglycerol (TAG) accumulation in nonadipose tissues, particularly in liver (27), is strongly associated with insulin resistance, suggesting the presence of a mechanistic link between hepatic lipid synthesis and insulin signaling. We have shown that the glycerolipid synthetic pathway initiated by the glycerol-3-phosphate acyltransferase isoform 1 (GPAT1) produces lipid intermediates that inhibit insulin signaling and impair the ability of insulin to diminish hepatic gluconeogenesis (22,39).The pathway of de novo TAG biosynthesis produces three potential signaling lipid intermediates, lysophosphatidic acid (LPA), phosphatidic acid (PA), and diacylglycerol (DAG). Glycerol 3-phosphate is acyla...

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Section: Di16:0-pa Increased In Hepatocytes Overexpressing Gpat4 and mentioning

confidence: 99%

Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

Zhang

Cooper

Grevengoed

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…19 Similarly, in the proGhrelin-expressing mHypoE-38 neurons 10 nM insulin caused a 40% decrease in preproghrelin mRNA expression at 2 hours post treatment (Fig. 1C).…”

Section: Insulin Signaling and Downstream Effects On Neuropeptide Mrnmentioning

confidence: 64%

“…2C) we evaluated the effects of insulin on four separate cell lines, the mHypoE-36/1, -38, -39 and mHypoE-46 neurons. [18][19][20] Insulin administration to the cell lines led to an increase in the anorexigenic NT; and a decrease in the orexigenic neuropeptides: NPY, AgRP and preproghrelin. Studies within the anorexigenic NT-expressing mHypoE-36/1 and mHypoE-39 neurons demonstrated an approximate 1.5-fold increase in NT mRNA levels following 10 or 100 nM treatment with insulin and α-MSH, but not NPY (Fig.…”

Section: Insulin Signaling and Downstream Effects On Neuropeptide Mrnmentioning

confidence: 99%

Nutrient sensing and insulin signaling in neuropeptide-expressing immortalized, hypothalamic neurons: A cellular model of insulin resistance

Fick¹,

Belsham²

2010

Cell Cycle

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O besity and type 2 diabetes mellitus represent a significant global health crisis. These two interrelated diseases are typified by perturbed insulin signaling in the hypothalamus. Using novel hypothalamic cell lines, we have begun to elucidate the molecular and intracellular mechanisms involved in the hypothalamic control of energy homeostasis and insulin resistance. In this review, we present evidence of insulin and glucose signaling pathways that lead to changes in neuropeptide gene expression. We have identified some of the molecular mechanisms involved in the control of de novo hypothalamic insulin mRNA expression. And finally, we have defined key mechanisms involved in the etiology of cellular insulin resistance in hypothalamic neurons that may play a fundamental role in cases of high levels of insulin or saturated fatty acids, often linked to the exacerbation of obesity and diabetes.

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“…Insulin binds to insulin receptors in peripheral tissues and triggers glucose uptake via insulin-sensitive glucose transporters. Insulin, together with the amylin released by the β-cells simultaneously with insulin (22), plays an important role in the regulation of appetite by suppressing orexic genes within the hypothalamus (23,24). In Akita mice, misfolded insulin protein causes ER stress and β-cell death, resulting in reduced insulin production (13).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA polymerase editing mutation, Polg ^D257A , reduces the diabetic phenotype of Akita male mice by suppressing appetite

Fox

Kim

Reddick³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes and the development of its complications have been associated with mitochondrial DNA (mtDNA) dysfunction, but causal relationships remain undetermined. With the objective of testing whether increased mtDNA mutations exacerbate the diabetic phenotype, we have compared mice heterozygous for the Akita diabetogenic mutation (Akita) with mice homozygous for the D257A mutation in mitochondrial DNA polymerase gamma (Polg) or with mice having both mutations (Polg-Akita). The Polg-D257A protein is defective in proofreading and increases mtDNA mutations. At 3 mo of age, the Polg-Akita and Akita male mice were equally hyperglycemic. Unexpectedly, as the Polg-Akita males aged to 9 mo, their diabetic symptoms decreased. Thus, their hyperglycemia, hyperphagia and urine output declined significantly. The decrease in their food intake was accompanied by increased plasma leptin and decreased plasma ghrelin, while hypothalamic expression of the orexic gene, neuropeptide Y, was lower and expression of the anorexic gene, proopiomelanocortin, was higher. Testis function progressively worsened with age in the double mutants, and plasma testosterone levels in 9-mo-old Polg-Akita males were significantly reduced compared with Akita males. The hyperglycemia and hyperphagia returned in aged Polg-Akita males after testosterone administration. Hyperglycemia-associated distal tubular damage in the kidney also returned, and Polg-D257A-associated proximal tubular damage was enhanced. The mild diabetes of female Akita mice was not affected by the Polg-D257A mutation. We conclude that reduced diabetic symptoms of aging Polg-Akita males results from appetite suppression triggered by decreased testosterone associated with damage to the Leydig cells of the testis. D iabetes mellitus is becoming increasingly common worldwide. A large body of data demonstrates links between mitochondrial dysfunction, insulin resistance, and diabetes (1, 2). Deleterious mitochondrial DNA (mtDNA) mutations have their greatest effect in cells that require high energy production, or already have high oxidative stress, including neurons, hair cells of the inner ears, heart and skeletal myocytes, pancreatic beta cells, and gut and kidney epithelial cells (3-7). Complications of diabetes also involve damage to these metabolically active cell types, leading to a hypothesis that mtDNA mutations contributes to the complications. Consistent with these findings, we have demonstrated in mice that a genetic absence of the bradykinin B2 receptor (B2R) combined with diabetes caused by the Akita mutation, Ins2 C96Y

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Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons

Cited by 82 publications

References 65 publications

Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

Nutrient sensing and insulin signaling in neuropeptide-expressing immortalized, hypothalamic neurons: A cellular model of insulin resistance

Mitochondrial DNA polymerase editing mutation, Polg ^D257A , reduces the diabetic phenotype of Akita male mice by suppressing appetite

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Insulin directly regulates NPY and AgRP gene expression via the MAPK MEK/ERK signal transduction pathway in mHypoE-46 hypothalamic neurons

Cited by 82 publications

References 65 publications

Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor

Nutrient sensing and insulin signaling in neuropeptide-expressing immortalized, hypothalamic neurons: A cellular model of insulin resistance

Mitochondrial DNA polymerase editing mutation, Polg D257A , reduces the diabetic phenotype of Akita male mice by suppressing appetite

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Mitochondrial DNA polymerase editing mutation, Polg ^D257A , reduces the diabetic phenotype of Akita male mice by suppressing appetite