Identification of a novel agonist of peroxisome proliferator-activated receptors alpha and gamma that may contribute to the anti-diabetic activity of guggulipid in Lep(ob)/Lep(ob) mice.

The ethyl acetate extract of the gum of the guggul tree, Commiphora mukul (guggulipid), is marketed for the treatment of dyslipidaemia and obesity. We have found that it protects Lep(ob)/Lep(ob) mice from diabetes and have investigated possible molecular mechanisms for its metabolic effects, in particular those due to a newly identified component, commipheric acid. Both guggulipid (EC(50)=0.82 microg/ml) and commipheric acid (EC(50)=0.26 microg/ml) activated human peroxisome proliferator-activated receptor alpha (PPARalpha) in COS-7 cells transiently transfected with the receptor and a reporter gene construct. Similarly, both guggulipid (EC(50)=2.3 microg/ml) and commipheric acid (EC(50)=0.3 microg/ml) activated PPARgamma and both promoted the differentiation of 3T3 L1 preadipocytes to adipocytes. Guggulipid (EC(50)=0.66 microg/ml), but not commipheric acid, activated liver X receptor alpha (LXRalpha). E- and Z-guggulsterones, which are largely responsible for guggulipid's hypocholesterolaemic effect, had no effects in these assays. Guggulipid (20 g/kg diet) improved glucose tolerance in female Lep(ob)/Lep(ob) mice. Pure commipheric acid, given orally (960 mg/kg body weight, once daily), increased liver weight but did not affect body weight or glucose tolerance. However, the ethyl ester of commipheric acid (150 mg/kg, twice daily) lowered fasting blood glucose and plasma insulin, and plasma triglycerides without affecting food intake or body weight. These results raise the possibility that guggulipid has anti-diabetic activity due partly to commipheric acid's PPARalpha/gamma agonism, but the systemic bioavailability of orally dosed, pure commipheric acid appears poor. Another component may contribute to guggulipid's anti-diabetic and hypocholesterolaemic activity by stimulating LXRalpha.

Improved glucose tolerance in acyl CoA:diacylglycerol acyltransferase 1-null mice is dependent on diet.

BACKGROUND: Mice that lack acyl CoA:diacylglycerol acyltransferase (Dgat1-/- mice) are reported to have a reduced body fat content and improved glucose tolerance and insulin sensitivity. Studies so far have focussed on male null mice fed a high fat diet and there are few data on heterozygotes. We compared male and female Dgat1-/-, Dgat1+/- and Dgat1+/+ C57Bl/6 mice fed on either standard chow or a high fat diet. RESULTS: Body fat content was lower in the Dgat1-/- than the Dgat1+/+ mice in both experiments; lean body mass was higher in male Dgat1-/- than Dgat1+/+ mice fed on the high fat diet. Energy intake and expenditure were higher in male Dgat1-/- than Dgat1+/+ mice; these differences were less marked or absent in females. The body fat content of female Dgat1+/- mice was intermediate between that of Dgat1-/- and Dgat1+/+ mice, whereas male Dgat1+/- mice were similar to or fatter than Dgat1+/+ mice. Glucose tolerance was improved and plasma insulin reduced in Dgat1-/- mice fed on the high fat diet, but not on the chow diet. Both male and female Dgat1+/- mice had similar glucose tolerance to Dgat1+/+ mice. CONCLUSION: These results suggest that although ablation of DGAT1 improves glucose tolerance by preventing obesity in mice fed on a high fat diet, it does not improve glucose tolerance in mice fed on a low fat diet.

Prevention of diet-induced obesity and impaired glucose tolerance in rats following administration of leptin to their mothers.

Absence of leptin is known to disrupt the development of energy balance regulatory mechanisms. We investigated whether administration of leptin to normally nourished rats affects energy balance in their offspring. Leptin (2 mg.kg(-1).day(-1)) was administered from day 14 of pregnancy and throughout lactation. Male and female offspring were fed either on chow or on high-fat diets that elicited similar levels of obesity in the sexes from 6 wk to 15 mo of age. Treatment of the dams with leptin prevented diet-induced increases in the rate of weight gain, retroperitoneal fat pad weight, area under the intraperitoneal glucose tolerance curve, and fasting plasma insulin concentration in female offspring. In the male offspring, the diet-induced increase in weight gain was prevented and increased fat pad weight was reduced. Energy intake per rat was higher in response to the obesogenic diet in male offspring of saline-treated but not leptin-treated dams. A similar trend was seen in 3-mo-old female offspring. Energy expenditure at 3 mo of age was higher for a given body weight in female offspring of leptin-treated compared with saline-treated dams when these animals were fed on the obesogenic diet. A similar trend was seen for male rats fed on the obesogenic diet. Thus leptin levels during pregnancy and lactation can affect the development of energy balance regulatory systems in their offspring.