Improvement of glucose homeostasis and hepatic insulin resistance in ob/ob mice given oral molybdate

Abstract

Molybdate (Mo) exerts insulinomimetic effects in vitro. In this study, we evaluated whether Mo can improve glucose homeostasis in genetically obese, insulin-resistant ob/ob mice. Oral administration of Mo (174 mg/kg molybdenum element) for 7 weeks did not affect body weight, but decreased the hyperglycaemia (approximately 20 mM) of obese mice to the levels of lean (L) (+/+) mice, and reduced the hyperinsulinaemia to one-sixth of pretreatment levels. Tolerance to oral glucose was improved: total glucose area was 30% lower in Mo-treated mice than in untreated ob/ob mice (O), while the total insulin area was halved. Hepatic glucokinase (GK) mRNA level and activity were unchanged in O mice compared with L mice, but the mRNA level and activity of L-type pyruvate kinase (L-PK) were increased in O mice by 3.5- and 1.7-fold respectively. Mo treatment increased GK mRNA levels and activity (by approximately 2.2-fold and 61% compared with O values), and had no, or only a mild, effect on the already increased L-PK variables. mRNA levels and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK) were augmented in O liver (sixfold and by 57% respectively), and these were reduced by Mo treatment. Insulin binding to partially purified receptors from liver was reduced in O mice and restored by Mo treatment. Despite this correction, overall receptor tyrosine kinase activity was not improved in Mo mice. Moreover, the overexpression (by two- to fourfold) of the cytokine tumour necrosis factor alpha (TNF alpha) in white adipose tissue, which may have a determinant role in the insulin resistance of the O mice, was unaffected by Mo. Likewise, overexpression of the ob gene in white adipose tissue was unchanged by Mo. In conclusion, Mo markedly improved glucose homeostasis in the ob/ob mice by an insulin-like action which appeared to be exerted distal to the insulin receptor tyrosine kinase step. The blood glucose-lowering effect of Mo was unrelated to over-expression of the TNF alpha and ob genes in O mice, but resulted at least in part from attenuation of liver insulin resistance by the reversal of pre-translational regulatory defects in these mice.

Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob/ob Mice

“…In the present study, we observed that leptin treatment of ob/ob and STZ-treated ob/ob mice causes marked elevation of hepatic 11␤-HSD1 expression, reduction of body weight and circulating corticosterone levels, and reversal of hyperglycemia within 2 weeks without the use of insulin. Moreover, we also observed that leptin treatment of ob/ob mice increased insulin sensitivity and reduced the expression of PEPCK, a gluconeogenic enzyme that is correlated with the acceleration of gluconeogenic pathways in the ob/ob mouse liver (48). These results provide new evidence that leptin plays insulin-independent roles in the control of glucose metabolism and that modulation of hepatic 11␤-HSD1 expression may be involved in the glucose-lowering effects of leptin in obese mice.…”

Hepatic VLDL Production in ob/ob Mice Is Not Stimulated by Massive De Novo Lipogenesis but Is Less Sensitive to the Suppressive Effects of Insulin

“…Female ob/ob mice have been used extensively in metabolic studies concerning hepatic (and muscle) insulin sensitivity (8,42). To be able to compare our data with published work, we chose to use female ob/ob mice for the current experiments.…”

“…The contribution of hepatic lipoprotein production to the development of hyperlipidemia in these mice is not clear. Hyperglycemia together with an increased glycolytic activity in ob/ob mice may lead to an increased availability of acetyl-CoA residues for DNL (7), as supported by increased hepatic expression levels and activities of glycolytic enzymes, i.e., glucokinase (8,9), phosphofructokinase (7), and pyruvate kinase (7,8). Furthermore, elevated plasma free fatty acid (FFA) levels (9) and increased hepatic expression of fatty acid translocase (FAT or CD36) and plasma membranefatty acid binding protein have been reported in this model (10).…”

Leptin treatment markedly increased plasma adiponectin but barely decreased plasma resistin of ob/ob mice

“…Blood glucose was measured using a glucometer (Elite, Bayer, Brussels, Belgium). Plasma insulin, corticosterone, total cholesterol, and triglyceride levels were determined as described (5,44). Protein concentrations in tissue homogenates were measured by the Bradford method.…”