Relationship between Milk Composition and Pup's Growth in Mice

Nagasawa, Hiroshi; Naito, Toshio; Kataoka, Kyoko

doi:10.3181/00379727-191-42892

Cited by 20 publications

(13 citation statements)

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“…2003) whereas heterozygous human female patients would be anticipated to have PDC‐deficient cells beginning at a late blastocyst stage when X chromosome inactivation occurs (Pereira and Vasques 2000); (ii) Cre br+ females have PDC deficiency limited to the cells of neuroectoderm (Tronche et al . 1999) whereas female patients have a more systemic deficiency that may result in greater physiologic stress (as demonstrated by the report of lactic acidemia in symptomatic human females whereas Cre br+ females have normal plasma lactic acid levels); (iii) mice may have a decreased dependence on glucose oxidation during the early post‐natal period due to the availability of ketone bodies from high fat content (13–21%, Nagasawa et al . 1989) in mouse milk compared to that of human (3.8%); and (iv) there may be an ascertainment bias that favors the recognition and reporting of more severe clinical cases.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency

Pliss¹,

Pentney²,

Johnson³

et al. 2004

Journal of Neurochemistry

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Pyruvate dehydrogenase complex (PDC) deficiency is an inborn metabolic disorder associated with a variety of neurologic abnormalities. This report describes the development and initial characterization of a novel murine model system in which PDC deficiency has been introduced specifically into the developing nervous system. The absence of liveborn male and a roughly 50% reduction in female offspring following induction of the X-linked mutation indicate that extensive deficiency of PDC in the nervous system leads to pre-natal lethality. Brain tissue from surviving females at post-natal days 15 and 35 was shown to have approximately 75% of wild-type PDC activity, suggesting that a threshold of enzyme activity exists for post-natal survival. Detailed histological analyses of brain tissue revealed structural defects such as disordered neuronal cytoarchitecture and neuropil fibers in grey matter, and reduced size of bundles and disorganization of fibers in white matter. Many of the histologic abnormalities resemble those found in human female patients who carry mutations in the X-linked ortholog. These findings demonstrate a requirement for PDC activity within the nervous system for survival in utero and suggest that impaired pyruvate metabolism in the developing brain can affect neuronal migration, axonal growth and cell-cell interactions. Keywords: animal models of metabolic diseases, brain development, glucose metabolism, lipid synthesis, pyruvate dehydrogenase deficiency.

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Section: Discussionmentioning

confidence: 99%

Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency

Pliss¹,

Pentney²,

Johnson³

et al. 2004

Journal of Neurochemistry

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“…white adipose tissue). Mouse milk is very low in sugar, containing only 2-5% of calories from lactose (25,26), and cannot supply the glucose needs of the animal. Additional glucose must be synthesized from glycerol and amino acids.…”

Section: Discussionmentioning

confidence: 99%

“…However, mouse milk derives only 16 -17% of its calories from protein and 2-5% from lactose, versus 26% and 8 -9%, respectively, for the rat (24,26,27). In neonatal animals, amino acids tend to be relatively spared as gluconeogenic substrates, because they are needed for growth (27,34).…”

Section: Discussionmentioning

confidence: 99%

Normal Thyroid Thermogenesis but Reduced Viability and Adiposity in Mice Lacking the Mitochondrial Glycerol Phosphate Dehydrogenase

Brown

Koza

Everett

et al. 2002

Journal of Biological Chemistry

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The mitochondrial glycerol phosphate dehydrogenase (mGPD) is important for metabolism of glycerol phosphate for gluconeogenesis or energy production and has been implicated in thermogenesis induced by cold and thyroid hormone treatment. mGPD in combination with the cytosolic glycerol phosphate dehydrogenase (cGPD) is proposed to form the glycerol phosphate shuttle, catalyzing the interconversion of dihydroxyacetone phosphate and glycerol phosphate with net oxidation of cytosolic NADH. We made a targeted deletion in Gdm1 and produced mice lacking mGPD. On a C57BL/6J background these mice showed a 50% reduction in viability compared with wild-type littermates. Uncoupling protein-1 mRNA levels in brown adipose tissue did not differ between mGPD knockout and control pups, suggesting normal thermogenesis. Pups lacking mGPD had decreased liver ATP and slightly increased liver glycerol phosphate. In contrast, liver and muscle metabolites were normal in adult animals. Adult mGPD knockout animals had a normal cold tolerance, normal circadian rhythm in body temperature, and demonstrated a normal temperature increase in response to thyroid hormone. However, they were found to have a lower body mass index, a 40% reduction in the weight of white adipose tissue, and a slightly lower fasting blood glucose than controls. The phenotype may be secondary to consequences of the obligatory production of cytosolic NADH from glycerol metabolism in the mGPD knockout animal. We conclude that, although mGPD is not essential for thyroid thermogenesis, variations in its function affect viability and adiposity in mice.The glycerol phosphate shuttle, composed of the FAD-dependent mitochondrial glycerol phosphate dehydrogenase (mGPD, 1 EC 1.1.99.5) and the NAD(H)-dependent cytosolic glycerol phosphate dehydrogenase (cGPD, EC 1.1.1.8), is generally considered to play a role in the oxidation of cytosolic NADH formed during glycolysis. In mice the mitochondrial enzyme is encoded by a single gene, Gdm1, on chromosome 2 (1). The cytosolic enzyme has both an adult form, encoded by Gdc1 on chromosome 15 (2) and an embryonic form, encoded by Gdc2 on chromosome 9 (3). The embryonic form has not been found in liver or kidney during gestation but persists in brain for several weeks following birth (4) and in the epididymal white adipose tissue until at least 5 days of age (5). It has recently been reported that mice lacking the adult form of cGPD have elevated dihydroxyacetone phosphate and decreased glycerol phosphate and ATP levels in muscle following exercise (6), although these mice otherwise appear normal, having normal weights and litter sizes (7). Surprisingly, these cGPD-deficient mice grow normally even on a diet essentially free of glycerol (6), presumably by using the dihydroxyacetone phosphate acyl transferase pathway for lipid synthesis. The findings suggest that a lack of cGPD alters the cellular redox status in muscle, whereas pancreatic islet function is relatively normal and liver is only mildly affected, confirming the ability of alter...

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“…Gluconeogenesis and the Importance of Glycerol-Glyceride glycerol is an especially important gluconeogenic precursor in the neonatal mouse, because 80% of calories from mouse milk are derived from fat, 16 -17% from protein, and only 2-5% from lactose (20,(22)(23)(24). Thus total calories available from dietary glycerol (ϳ4%) equal calories from lactose.…”

Section: Discussionmentioning

confidence: 99%

Lethal Hypoglycemic Ketosis and Glyceroluria in Mice Lacking Both the Mitochondrial and the Cytosolic Glycerol Phosphate Dehydrogenases

Brown

Koza

Marshall

et al. 2002

Journal of Biological Chemistry

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The activities of either the mitochondrial or cytosolic glycerol phosphate dehydrogenase (mGPD, cGPD) plus that of glycerol kinase are required for the use of glycerol in aerobic metabolism and gluconeogenesis. A knockout mouse lacking mGPD has reduced body weight and fertility but shows remarkably normal liver and muscle metabolite levels. The BALB/cHeA mouse strain, which lacks cGPD, breeds well and is phenotypically normal, although it demonstrates metabolite abnormalities in certain tissues. Crosses were made between these two strains, and mice were generated that lacked both dehydrogenases. These mice, although active and nursing well for several days, failed to grow, and usually died within the first week. Liver glycerol phosphate levels were elevated 30-fold, whereas liver ATP, ADP, and AMP levels were reduced by 30 -40%. Plasma glycerol was elevated 30-to 50-fold to 30 -50 mM, and urine glycerol exceeded 0.45 M (4% w/v). GPD-deficient mice were hypoglycemic, had a 50% increase in plasma free fatty acids, and developed ketonuria within the first day of life. Uncoupling protein-1 mRNA in brown adipose tissue was reduced 60%. These mice share some features of both glycerol kinase deficiency and hereditary fructose intolerance, suggesting the phenotype may be due to the combined effects of the loss of a gluconeogenic substrate, the osmotic effects of glycerol, and the metabolic effects of the accumulation of a phosphorylated metabolite.Mammalian cells contain two glycerol phosphate dehydrogenase enzymes. The NADH-dependent cytosolic enzyme (EC 1.1.1.8) catalyzes the conversion of dihydroxyacetone phosphate (DHAP) 1 to glycerol phosphate. This reaction is reversible, with a strong preference under physiologic conditions for the production of glycerol phosphate. In the mouse, this enzyme is encoded by Gdc1. An embryonic form of the enzyme is encoded by Gdc2 but has not been found in liver or kidney during gestation, although it persists in brain of the neonate for several weeks (1) and in epididymal white fat for at least 5 days after birth (2). The FAD-dependent mitochondrial GPD (EC 1.1.99.5) is encoded by a single gene, Gdm1, on chromosome 2 (3) and is located on the outer surface of the mitochondrial inner membrane. mGPD catalyzes the irreversible conversion of glycerol phosphate to DHAP, with transfer of electrons from bound FAD through ubiquinone to complex III of the electron transport chain. These two enzymes form the glycerol phosphate shuttle, which cycles glycerol phosphate and DHAP to oxidize NADH formed in the cytosol. A spontaneous mutation in Gdc1 in the inbred strain BALB/cHeA results in an altered mRNA size and the loss of cGPD enzyme activity (4). cGPD-deficient BALB/cHeA animals are viable and fertile, although they demonstrate some evidence of an inhibition of glycolysis at glyceraldehyde phosphate dehydrogenase in skeletal muscle (5). We (40) and others (6) have produced knockout mice-deficient in mGPD. The mGPD knockout mice have decreased adiposity and reduced fertility and viability (40...

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Relationship between Milk Composition and Pup's Growth in Mice

Cited by 20 publications

References 1 publication

Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency

Biochemical and structural brain alterations in female mice with cerebral pyruvate dehydrogenase deficiency

Normal Thyroid Thermogenesis but Reduced Viability and Adiposity in Mice Lacking the Mitochondrial Glycerol Phosphate Dehydrogenase

Lethal Hypoglycemic Ketosis and Glyceroluria in Mice Lacking Both the Mitochondrial and the Cytosolic Glycerol Phosphate Dehydrogenases

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