Mouse Lacking NAD+-Linked Glycerol Phosphate Dehydrogenase Has Normal Pancreatic Beta Cell Function But Abnormal Metabolite Pattern in Skeletal Muscle

MacDonald, Michael J.; Marshall, Linda K.

doi:10.1006/abbi.2000.2107

Cited by 70 publications

(49 citation statements)

References 29 publications

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“…This, in turn, reduces the accumulation of lactate and is associated with increased heat production relative to tissues that use predominantly the malate-aspartate shuttle. The importance of the G3P shuttle for muscle is evidenced by the increase in DHAP and decrease in G3P observed in muscle but not in liver of mice with cGPD deficiency (30,31) and is further demonstrated here.…”

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confidence: 69%

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Mice with deletion of the mitochondrial glycerol-3-phosphate dehydrogenase gene exhibit a thrifty phenotype: effect of gender

Alfadda¹,

DosSantos²,

Stepanyan³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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To define the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPD; EC 1.1.99.5) in energy balance and intermediary metabolism, we studied transgenic mice not expressing mGPD (mGPDϪ/Ϫ). These mice had Ϸ14% lower blood glucose; Ϸ50% higher serum glycerol; Ϸ80% higher serum triglycerides; and at thermoneutrality, their energy expenditure (QO2) was 15% lower than in wild-type (WT) mice. Glycerol-3-phosphate levels and lactate-to-pyruvate ratios were threefold elevated in muscle, but not in liver, of mGPDϪ/Ϫ mice. WT and mGPDϪ/Ϫ mice were then challenged with a high-fat diet, fasting, or food restriction. The high-fat diet caused more weight gain and adiposity in mGPDϪ/Ϫ than in WT female mice, without the genotype differentially affecting QO2 or energy intake. After a 30-h fast, WT female lost 60% more weight than mGPDϪ/Ϫ mice but these latter became more hypothermic. When energy intake was restricted to 50 -70% of the ad libitum intake for 10 days, mGPDϪ/Ϫ female mice lost less weight than WT controls, but they had lower QO 2 and body temperature. WT and mGPDϪ/Ϫ male mice did not differ significantly in their responses to these challenges. These results show that the lack of mGPD causes significant alterations of intermediary metabolism, which are more pronounced in muscle than liver and lead to a thrifty phenotype that is more marked in females than males. Lower T 4-to-T3 conversion in mGPDϪ/Ϫ females and a greater reliance of normal females on mGPD to respond to high-fat diets make the lack of the enzyme more consequential in the female gender. NADH shuttles; thermogenesis; obesity; high-fat diets; intermediary metabolism OBESITY IS A GROWING HEALTH problem, already of alarming proportions in Western societies. Although it is true that environmental factors are of great importance, the susceptibility of individuals to develop obesity on a comparable level of overfeeding as well as the capacity to lose weight in response to caloric restriction are quite variable due to genetic factors (1, 2). We report here that the deletion of the mitochondrial glycerol 3-phosphate dehydrogenase (mGPD; EC 1.1.99.5) gene is associated with a thrifty phenotype, characterized by a greater weight gain when these mice are fed a high-fat diet and a smaller weight loss when they are submitted to fasting or food restriction. Such a phenotype is restricted to females.The cleavage of fructose-1,6-diphosphate into two 3-carbon molecules, dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate, is a critical point in the glycolytic pathway. DHAP can be converted into glyceraldehyde-3-phosphate by a triose phosphate isomerase and thus continue in the glycolytic pathway, but it can also serve as acceptor of reducing equivalents (H ϩ , e Ϫ ) generated in the cytoplasm and transferred from NADH [and NADPH (11)], in a reaction catalyzed by the cytoplasmic glycerol-3-phosphate dehydrogenase (cGPD; EC 1.1.1.8). The resulting glycerol-3-phosphate (G3P) is reoxidized to DHAP by the mGPD. This enzyme is a flavin adenine dinucleotid...

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confidence: 69%

“…For one thing, both mGPD and cGPD activities are normally four-to fivefold higher in muscle (Table 4 and Ref. 30), indicating proportionally more active fluxes. Second, the malate-aspartate NADH shuttle is very active in the liver, whereas its activity is minimal in skeletal muscle (26).…”

Section: Discussionmentioning

confidence: 99%

Mice with deletion of the mitochondrial glycerol-3-phosphate dehydrogenase gene exhibit a thrifty phenotype: effect of gender

Alfadda¹,

DosSantos²,

Stepanyan³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Indeed, in a mouse model of GPD1 deficiency, DHAP concentrations were significantly higher, and G3P lower when compared with the levels in WT mice in liver, muscle, and kidneys. 10 The mechanism of fatty liver in our patient may be due to acylation of excess DHAP. An acyl-DHAP pathway has been previously described where DHAP may first be acylated followed by reduction to 1-acyl-sn-G3P.…”

Section: Discussionmentioning

confidence: 70%

A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia

et al. 2014

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The constellation of clinico-pathological and laboratory findings including massive hepatomegaly, steatosis, and marked hypertriglyceridemia in infancy is extremely rare. We describe a child who is presented with the above findings, and despite extensive diagnostic testing no cause could be identified. Whole exome sequencing was performed on the patient and parents' DNA. Mutations in GPD1 encoding glycerol-3-phosphate dehydrogenase that catalyzes the reversible redox reaction of dihydroxyacetone phosphate and NADH to glycerol-3-phosphate (G3P) and NAD þ were identified. The proband inherited a GPD1 deletion from the father determined using copy number analysis and a missense change p.(R229Q) from the mother. GPD1 protein was absent in the patient's liver biopsy on western blot. Low normal activity of carnitine palmitoyl transferases, CPT1 and CPT2, was present in the patient's skin fibroblasts, without mutations in genes encoding for these proteins. This is the first report of compound heterozygous mutations in GPD1 associated with a lack of GPD1 protein and reduction in CPT1 and CPT2 activity.

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“…Type II muscle fibers are predominantly glycolytic and express mGPDH and, at rest, will have adequate glycerol 3-phosphate and free calcium in the cytosol to drive mitochondrial oxidation of glycerol 3-phosphate (55)(56)(57)(58)(59). Therefore, it is expected that mGPDH will produce superoxide even in resting muscle.…”

Section: Discussionmentioning

confidence: 99%

A Refined Analysis of Superoxide Production by Mitochondrial sn-Glycerol 3-Phosphate Dehydrogenase

Orr

Quinlan

Perevoshchikova

et al. 2012

Journal of Biological Chemistry

149

118

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Background: Oxidation of glycerol 3-phosphate generates superoxide/H 2 O 2 from multiple sites within mitochondria. Results: Some of the superoxide/H 2 O 2 originates specifically from mGPDH, but much can come from complex II; this demands a reassessment of prior investigations. Conclusion:The ubiquinone binding site in mGPDH produces superoxide to both sides of the inner membrane. Significance: mGPDH can generate superoxide at rates comparable with other major sites.

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Mouse Lacking NAD+-Linked Glycerol Phosphate Dehydrogenase Has Normal Pancreatic Beta Cell Function But Abnormal Metabolite Pattern in Skeletal Muscle

Cited by 70 publications

References 29 publications

Mice with deletion of the mitochondrial glycerol-3-phosphate dehydrogenase gene exhibit a thrifty phenotype: effect of gender

Mice with deletion of the mitochondrial glycerol-3-phosphate dehydrogenase gene exhibit a thrifty phenotype: effect of gender

A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia

A Refined Analysis of Superoxide Production by Mitochondrial sn-Glycerol 3-Phosphate Dehydrogenase

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