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    • Dgat mice however had less

    2020-11-25

    Dgat−/− mice, however, had less adipose tissue, as reflected by lower total fat pad weights and body triglyceride content. Because of these findings, we hypothesized that, although Dgat−/− mice could make triglycerides through non-DGAT pathway(s), their triglyceride synthesis capacity might not be equivalent to that of wild-type mice. To test this hypothesis, Dgat−/− mice were fed a high-fat diet (21% fat by weight). Whereas DGAT wild-type and heterozygous mice increased their weight by 40–50%, on this diet Dgat−/− mice maintained weights comparable to those of mice fed the regular chow diet (Figure 3A). This weight difference resulted primarily from a ∼40% decrease in total carcass triglycerides in Dgat−/− mice (Figure 3B); carcass protein content, reflecting lean body mass, was similar in both groups of mice. Thus, Dgat−/− mice had less adipose tissue than wild-type mice at baseline and were resistant to diet-induced obesity.
    DGAT Deficiency Increases Energy Expenditure in Mice Two possible mechanisms for the obesity resistance in DGAT deficiency were investigated: decreased caloric intake and increased energy expenditure. Although DGAT is highly expressed in the small intestine and has been hypothesized to play an important role in the SC 79 mg of dietary triglycerides, DGAT deficiency did not impair caloric absorption, even when the mice were fed a high-fat diet. Also, food intake was not decreased in Dgat−/− mice. Thus, there was no evidence for decreased caloric intake. However, when we measured energy expenditure by indirect calorimetry (through continuous monitoring of O2 consumption and CO2 production), we unexpectedly found that the metabolic rate was ∼20% higher in Dgat−/− mice than in wild-type mice on both regular and high-fat diets (Smith et al. 2000). How does DGAT deficiency increase energy expenditure? Although the exact mechanism is currently unknown, increased physical activity in Dgat−/− mice partially accounts for their increased energy expenditure. On the high-fat diet, Dgat−/− mice were approximately twice as active as wild-type mice. These findings raise the intriguing possibility that DGAT deficiency protects against obesity in part by enhancing physical activity in response to increased fat intake, thereby “burning off” the additional caloric intake. This phenomenon is reminiscent of the increased non-exercise activity observed in some non-obese humans when they consumed excess calories (Levine et al. 1999). Activity levels were not increased in Dgat−/− mice fed the chow diet, even though their metabolic rates were higher. This result implies that at least one alternative mechanism mediates the increased energy expenditure of Dgat−/− mice in the basal, chow-fed state.
    Unanswered Questions Concerning DGAT Deficiency and Energy Expenditure How DGAT deficiency leads to increased physical activity and what alternative mechanisms mediate the increased energy expenditure in DGAT deficiency are currently unknown. Several possibilities, including hyperthyroidism and hyperleptinemia, have been excluded (Smith et al. 2000). Current studies are investigating whether increased thermogenesis (e.g., through increased uncoupling protein activity) or β-oxidation of fatty acids contributes to the increased energy expenditure. DGAT deficiency is also being introduced into mouse genetic models of obesity (e.g., leptin-deficient mice) through breeding. These genetic models should yield additional insights into both the magnitude of the obesity resistance in DGAT deficiency and possible contributing mechanisms.
    DGAT Deficiency Improves Glucose Metabolism In addition to affecting energy expenditure, DGAT deficiency appeared to alter glucose metabolism in mice. Dgat−/− mice had normal basal levels of plasma glucose and insulin. However, when subjected to a glucose load, Dgat−/− mice tended to have lower glucose and insulin levels than wild-type mice, suggesting improved glucose metabolism in DGAT deficiency. Moreover, preliminary observations indicate that DGAT deficiency significantly lowers serum insulin levels in Agouti yellow mice (H. Chen and R. Farese, Jr., unpublished data), which are genetically obese and insulin resistant. The improved glucose metabolism in Dgat−/− mice contrasts with the insulin resistance observed in other murine models with severely reduced adipose tissue Moitra et al. 1998, Shimomura et al. 1998.