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

Abstract

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...

A high carbohydrate diet does not induce hyperglycaemia in a mitochondrial glycerol-3-phosphate dehydrogenase-deficient mouse

“…Although several previous reports have described mGPDH -/-mice as normal [14,15,16,17], our results showed that the blood concentrations of triglycerides and cholesterol in mGPDH -/-mice are increased. These results could be due to the absence of mGPDH activity in the liver, but not in the pancreas.…”

“…The lower body weight showed by the mGPDH -/-mice was already reported in the papers describing the mGPDH knockouts [14,15], and our data agree with the percentage reported in those papers. Moreover, the high carbohydrate diet induces an increase in the thermogenesis, and the mice show a lower weight gain compared to standard diet [31], similar to what we observed in our experiments.…”

“…Therefore, the lack of mGPDH -could modify the NADH shuttle in the liver altering lipid metabolism. In mGPDH -/-mice, the NE-FA concentrations remain unchanged [15], which is consistent with our findings.…”

“…These results could be due to the absence of mGPDH activity in the liver, but not in the pancreas. Tough liver has lower concentrations of mGPDH compared to beta cell; in mGPDH -/-mice, lower concentrations of liver ATP and glycerol phosphate has been found recently [15]. Therefore, the lack of mGPDH -could modify the NADH shuttle in the liver altering lipid metabolism.…”

“…Therefore, several authors have suggested that mGPDH could play an important role in the pathogenesis of Type 2 diabetes [11,12,13]. To determine the role of the glycerol-3-phosphate shuttle in glucose-induced insulin secretion, mice with a targeted disruption of the mGPDH gene were generated [14,15]. mGPDH -/-knockout mice are not diabetic, only when the activities of both shuttles are halted by the use of aminooxyacetate, to block the malate-aspartate shuttle, are insulin secretion, glucose metabolism, and calcium oscillations severely impaired [16,17].…”