Lipid metabolism and body composition in Gclm(−/−) mice

Abstract

In humans and experimental animals, high fat diets (HFD) are associated with risk factors for metabolic diseases, such as excessive weight gain and adiposity, insulin resistance and fatty liver. Mice lacking the glutamate-cysteine ligase modifier subunit gene (Gclm(−/−)) and deficient in glutathione (GSH), are resistant to HFD-mediated weight gain. Herein, we evaluated Gclm-associated regulation of energy metabolism, oxidative stress, and glucose and lipid homeostasis. C57BL/6J Gclm(−/−) mice and littermate wild-type (WT) controls received a normal diet or a HFD for 11 weeks. HFD-fed Gclm(−/−) mice did not display a decreased respiratory quotient, suggesting that they are unable to process lipid for metabolism. Although dietary energy consumption and intestinal lipid absorption were unchanged in Gclm(−/−) mice, feeding these mice a HFD did not produce excess body weight nor fat storage. Gclm(−/−) mice displayed higher basal metabolic rates resulting from higher activities of liver mitochondrial NADH-CoQ oxidoreductase, thus elevating respiration. Although Gclm(−/−) mice exhibited strong systemic and hepatic oxidative stress responses, HFD did not promote glucose intolerance or insulin resistance. Furthermore, HFD-fed Gclm(−/−) mice did not develop fatty liver, likely resulting from very low expression levels of genes encoding lipid metabolizing enzymes. We conclude that Gclm is involved in the regulation of basal metabolic rate and the metabolism of dietary lipid. Although Gclm(−/−) mice display a strong oxidative stress response, they are protected from HFD-induced excessive weight gain and adipose deposition, insulin resistance and steatosis.

Reprint of “In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective”

“…The trend toward increased Pparg expression in wild type females exposed to BaP in utero is consistent with their increased hepatic oil red O staining (Sections 3.2 and 3.3). Interestingly and consistent with two recent reports that Gclm −/− mice are resistant to the induction of nonalcoholic hepatic steatosis by both a high fat diet (Kendig et al, 2011) and by a methionine and choline deficient diet (Haque et al, 2010), we observed minimal hepatic lipid despite upregulation of hepatic Pparg expression in female Gclm −/− livers. Our results add prenatal exposure to BaP to the list of stimuli of hepatic steatosis to which the Gclm null mice are resistant.…”

“…Our previous studies showed that Gclm −/− mice are more sensitive to the gonadal toxicity of gestational exposure to BaP than wild type littermates (Lim et al, 2013;Nakamura et al, 2012) and that female Gclm −/− mice are subfertile (Nakamura et al, 2011). In contrast, Gclm null mice are protected against diet-induced steatohepatitis, showing upregulation of hepatic antioxidant genes and downregulation of triglyceride synthesis and fatty acid ␤-oxidation (Haque et al, 2010;Kendig et al, 2011). Nonalcoholic hepatic steatosis, also called nonalcoholic fatty liver disease, is an independent risk factor for Type 2 diabetes and is prevalent in individuals with metabolic syndrome (Sung and Kim, 2011).…”

Emerging Role of Nrf2 in Adipocytes and Adipose Biology

“…Not surprisingly, mice lacking GCLM, the regulatory subunit of the glutamate-cysteine ligase enzyme involved in GSH synthesis, also display a resistance to high-fat diets (21). GCLM knockout mice had a lower weight when fed a high-fat diet, an increase in oxygen consumption, decreased hepatic lipid accumulation, and maintenance of insulin sensitivity.…”

Exploring the Lean Phenotype of Glutathione-Depleted Mice: Thiol, Amino Acid and Fatty Acid Profiles

“…These are mice in which glutamate cysteine ligase (GCL), the rate-limiting GSH synthesis enzyme, is inhibited by a genetic defect (GCL-modifier subunit knockout, Gclm -/- ) [11, 12] or by buthionine sulfoximine (BSO) [13, 14]. Gclm -/- mice also exhibit protection against fatty liver, and hepatic suppression of the lipogenic enzyme stearoyl CoA desaturase-1 (SCD1) [11, 12], but these features have not been tested in BSO-treated mice. As proposed by Kendig et al , GSH depletion is unlikely to be the cause of obesity-resistance conferred by GCL inhibition [11].…”