Stephen C. Blair

Differences in lipogenesis in tissues of control and gold-thioglucose obese mice after an isocaloric meal

Lipogenesis was measured in 2 and 5 week gold-thioglucose (GTG) obese mice after a single meal of 0.5 g of standard chow. Compared to control mice the rate of lipogenesis in GTG obese mice, was 4-fold higher in liver and 10-fold higher in white adipose tissue (WAT). In brown adipose tissue (BAT) of GTG-injected mice the lipogenic rate was only 50% of that of controls. These results indicate that the increased lipid synthesis observed in GTG-injected mice is not due solely to hyperphagia and that some other stimuli, such as increased basal insulin levels and/or decreased thermogenesis and insulin resistance in BAT, contribute to the high rates of fat synthesis in this animal model of obesity.

Insulin Response to an Intravenous Glucose Load During Development of Obesity in Gold Thioglucose-Injected Mice

The insulin secretory response to an intravenous glucose load was examined in chronically catheterized, conscious mice 2, 5, and 10 wk after induction of obesity by a single injection of gold thioglucose. At 2 wk after administration of gold thioglucose, a significant increase in both the insulinemia and incremental area under the curve of insulin release after intravenous glucose were observed (incremental area under the curve for 2-wk control mice, 852 ± 54 min/pM; incremental area under the curve for 2-wk GTG-injected mice, 1140 ± 114 min/pM; P < 0.05). At this stage, no significant difference existed in the glucose tolerance or body weight of control and gold thioglucose-injected mice. By 5 wk, the gold thioglucose-injected mice were ∼33% heavier than their lean controls and showed a marked glucose intolerance. This was accompanied by overt hyperinsulinemia in both the basal state and also in response to an intravenous glucose bolus as indicated by the increase in the incremental area under the curve of insulin (5-wk control mice, 816 ± 114 min/pM; 5-wk gold thioglucose-injected mice, 1374 ± 156 min/pM; P < 0.05). At 10 wk after gold thioglucose administration, body weight and the degree of glucose intolerance were increased. Although 10-wk gold thioglucose-injected mice showed basal hyperinsulinemia, an intravenous glucose bolus elicited a smaller insulin secretory response than that observed in the age-matched lean control animals (10-wk control mice, 672 ± 54 min/pM; 10-wk gold-thioglucose-injected mice 186 ± 42 min/pM; P < 0.05). Thus, during the early stages of gold thioglucose-induced obesity, a marked increase in insulin secretion in response to an intravenous glucose load occurs, but as the animals become chronically hyperinsulinemic and hyperglycemic, the insulin secretory response to intravenous glucose decreases, possibly indicating glucose toxicity of the pancreas. The increase in insulin secretion observed in 2-wk gold thioglucose-injected animals may be an important abnormality in the initiation of obesity responsible for the onset of the hyperlipogenesis and insulin resistance in this animal model.

Glucose and lipid metabolism in the gold thioglucose injected mouse model of diabesity

Gold thioglucose (GTG) (C6H11O5SAu) was initially developed and marketed as a therapeutic agent for the treatment of arthritis and rheumatism (Fig. 1). During toxicology studies, it was noted by Brecher and Waxier1 that a single i.p. or s.c. injection of GTG induced a syndrome of hyperphagia and obesity in mice. This observation was subsequently confirmed by Marshall and colleagues,2 who reported that GTG induced bilateral necrosis of the ventromedial hypothalamus (VMH) region of the brain and caused damage to the supraoptic nuclei, ventromedial nuclei, arcuate nuclei, and median eminence. These GTG-induced lesions in the hypothalamus of mice did not appear to impair central functions other than the regulation of food intake and body wt.3 The degree of obesity induced by GTG in mice is dependent on the dose of GTG administered and the particular strain of mice used.2,4 In general, the larger the dose of GTG administered, the greater the gain in body wt.5 Administration of a range of doses of GTG has been shown to induce variable wt gain and mortality in the C58, RIII, DBA, and BALB/C strains of mice compared with the CBA strain. CBA mice appear to be unique in that they exhibit a uniform response with respect to these two parameters.6