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

Abstract

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...

Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity

“…It therefore appears that Pten deletion may produce some different physiological effects dependent on gender. Although the underlying mechanism for this phenomenon is not clear at this point, our data are consistent with multiple knockout experiments targeting signaling pathways involved in the regulation of energy homeostasis that yielded as-yet unexplained gender-specific phenotypes (41)(42)(43). Thus, this is an area that clearly deserves further detailed analysis.…”

Thyroid Hormone and the Energetic Cost of Keeping Body Temperature

“…In rodents, mGPD is highly expressed in BAT (Ohkawa et al, 1969). In the mouse, skeletal muscle ranks second, next to BAT in mGPD abundance, followed by brain, kidney and liver (Koza et al, 1996), which we have just confirmed (Alfadda et al, 2004). This hierarchy is similar in the rat (Lee and Lardy, 1965).…”

“…Results have been recently published (Alfadda et al, 2004;DosSantos et al, 2003). The most salient characteristics of the phenotype are summarized in Table 1.…”

“…Consistent with the G3P shuttle being more active in muscle, G3P levels and lactate-to-pyruvate ratio were elevated in muscle, but not in liver. Actually, in liver the lactate-to-pyruvate ratio was reduced probably due to large influx of lactate and the large capacity of the liver to oxidize it to pyruvate, dumping the reducing equivalents into the mitochondria via the malateaspartate shuttle (Alfadda et al, 2004). Most interesting for this discussion, mGPD-/-mice had 15À20% higher levels of both T 4 and T 3 , which was due to increased thyroidal secretion, as plasma binding or clearance were not affected by the deletion of the mGPD gene.…”

“…Results showed (Alfadda et al, 2004) Reduced energy intake and expenditure (5À10%) Reduced size (5À15%) Reduced blood glucose (15%) Increased plasma triglycerides (30À50%) Increased blood G3P Increased skeletal muscle G3P and lactate-to-pyruvate ratio Increased circulating levels of T 4 and T 3 (15À20%) when reared at room temperature. T 3 only in males Evidence of chronic BAT stimulation when reared at room temperature Increased in UCP3 mRNA in skeletal muscle only in males References: (Alfadda et al, 2004;DosSantos et al, 2003). that mGPD-/-mice increased weight more rapidly than WT controls when challenged with a high fat diet, even though the caloric intake was not different from that of WT.…”