Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus.

To define the mechanisms of impaired muscle glycogen synthase and reduced glycogen formation in non-insulin dependent diabetes mellitus (NIDDM), glycogen synthase activity was kinetically analyzed during the basal state and three glucose clamp studies (insulin approximately equal to 300, 700, and 33,400 pmol/liter) in eight matched nonobese NIDDM and eight control subjects. Muscle glycogen content was measured in the basal state and following clamps at insulin levels of 33,400 pmol/liter. NIDDM subjects had glucose uptake matched to controls in each clamp by raising serum glucose to 15-20 mmol/liter. The insulin concentration required to half-maximally activate glycogen synthase (ED50) was approximately fourfold greater for NIDDM than control subjects (1,004 +/- 264 vs. 257 +/- 110 pmol/liter, P less than 0.02) but the maximal insulin effect was similar. Total glycogen synthase activity was reduced approximately 38% and glycogen content was approximately 30% lower in NIDDM. A positive correlation was present between glycogen content and glycogen synthase activity (r = 0.51, P less than 0.01). In summary, defects in muscle glycogen synthase activity and reduced glycogen content are present in NIDDM. NIDDM subjects also have less total glycogen synthase activity consistent with reduced functional mass of the enzyme. These findings and the correlation between glycogen synthase activity and glycogen content support the theory that multiple defects in glycogen synthase activity combine to cause reduced glycogen formation in NIDDM.

Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake.

To examine whether reduced rates of oxidative (Gox) and non-oxidative (Nox) glucose metabolism in non-insulin-dependent diabetes mellitus (NIDDM) are due to reduced glucose uptake, intrinsic defects in intracellular glucose metabolism or increased fat oxidation (Fox), indirect calorimetry was performed at similar glucose uptake rates in eight nonobese NIDDM and eight comparable nondiabetic subjects. Three glucose clamp studies were performed: one in the nondiabetic and two in the NIDDM subjects. In the nondiabetic subjects, glucose uptake was increased to 7.62 +/- 0.62 mg/kg of fat-free mass (FFM) per min by increasing serum insulin to 309 pmol/liter at a glucose concentration of 5.1 mmol/liter. By raising the concentration of either serum glucose or insulin fourfold in the NIDDM subjects, glucose uptake was matched to nondiabetic subjects (8.62 +/- 0.49 and 8.59 +/- 0.51 mg/kg FFM per min, respectively, P = NS). Skeletal muscle glycogen synthase activity and plasma lactate levels were measured to characterize Nox. When glucose uptake was matched to nondiabetics by hyperglycemia or hyperinsulinemia, Gox was reduced by 26-28% in NIDDM (P less than 0.025) whereas Fox was similar. Nox was greater in NIDDM (P less than 0.01) and was accompanied by increases in circulating lactate levels. Glycogen synthase activity was reduced by 41% (P less than 0.025) when glucose uptake was matched by hyperglycemia. Glycogen synthase activity was normalized in NIDDM, however, when glucose uptake was matched by hyperinsulinemia. Therefore, a defect in Gox exists in nonobese NIDDM subjects which cannot be overcome by increasing glucose uptake or insulin. Since both glucose uptake and Fox were similar in the two subject groups these factors were not responsible for reduced Gox. Increased Nox in NIDDM is primarily into lactate. Reduced glycogen synthase activity in NIDDM is independent of glucose uptake but can be overcome by increasing the insulin concentration.

Prevalence of obesity in Australia.

Australia is a large country approximately equal in area to mainland United States. The relatively small population of around 20 million are composed primarily of Caucasians. Extensive immigration from many different countries has made Australia one of the most culturally diverse populations in the world. Indigenous Australians make up only 2.4% of the total population. Australia has a prosperous Western-style capitalist economy, and spends approximately 830 million dollars on the direct health care costs of obesity. For Australians, it is now more common to have a weight problem, with overweight affecting 48% of men and 30% of women and obesity affecting a further 19% of men and 22% of women. This paper reports on recent epidemiological studies documenting the extent of overweight and obesity in adults and children in Australia.

Effect of hyperinsulinemia and hyperglycemia on intracellular glucose and fat metabolism in healthy subjects.

Hyperinsulinemia and hyperglycemia per se both stimulate glucose uptake and the disposal of glucose by oxidative (Gox) and nonoxidative (Nox) metabolism. However, the intracellular metabolic fate of glucose may not be the same when glucose uptake is stimulated predominantly by either of these mechanisms due to different effects on fat oxidation (Fox). To address this issue, 11 healthy subjects each had four glucose-clamp studies performed in combination with indirect calorimetry to compare Gox, Nox, and Fox at two different rates of glucose uptake (approximately 7 and 10 mg.kg-1 fat-free mass [FFM].min-1) matched at each level by either hyperglycemia or hyperinsulinemia. When glucose uptake was matched at the lower rate (7 mg.kg-1 FFM.min-1), there was less suppression of both FFA (33 vs. 43%, P less than 0.05) and Fox (73 vs. 90%, P less than 0.05) and less stimulation of incremental (above basal) Gox (1.95 vs. 2.49 mg.kg-1 FFM.min-1, P less than 0.025) at low insulin (72 pM) and hyperglycemia (21.8 mM) compared with high insulin (280 pM) and euglycemia (5.1 mM). Matching glucose uptake at the higher rates (10 mg.kg-1 FFM.min-1) required greater than 300 pM of insulin (309 and 632 pM) in both studies and resulted in maximal suppression of FFA (49 vs. 46%, NS) and Fox (both greater than 90%, NS) and similar incremental Gox (2.89 vs. 2.73 mg.kg-1 FFM.min-1, NS) whether at hyperglycemia (15.7 mM) or euglycemia (5.2 mM). Therefore, both hyperinsulinemia and hyperglycemia stimulate glucose uptake and increase intracellular glucose availability, but insulin also regulates Gox by suppression of FFA and Fox. However, when FFA and Fox are maximally suppressed, the rate of glucose uptake, rather than the prevailing insulin level, determines the distribution of intracellular glucose metabolism.

Metabolic effects of hyperglycemia and hyperinsulinemia on fate of intracellular glucose in NIDDM.

Hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) stimulates peripheral glucose uptake, which tends to compensate for impaired insulin-mediated glucose uptake. The metabolic fate of glucose and suppression of fat oxidation may differ, however, when glucose uptake is stimulated primarily by insulin or hyperglycemia. To address this issue, three hyperinsulinemic glucose-clamp studies were performed in combination with indirect calorimetry in seven nonobese subjects with NIDDM. In the first two experiments, when glucose uptake was matched at approximately 8 mg.kg-1 fat-free mass (FFM).min-1 with primarily hyperinsulinemia (1350 +/- 445 pM) or hyperglycemia (20.8 +/- 1.8 mM), identical rates of glucose oxidation (3.21 +/- 0.29 and 3.10 +/- 0.23 mg.kg-1 FFM.min-1, NS) and nonoxidative glucose metabolism (5.19 +/- 0.75 and 5.46 +/- 0.61 mg.kg-1 FFM.min-1, NS) were achieved. When glucose uptake was increased further to 11.11 +/- 0.36 mg.kg-1 FFM.min-1 with less insulin (625 +/- 70 pM) and hyperglycemia, glucose oxidation (3.85 +/- 0.26 mg.kg-1 FFM.min-1) and nonoxidative glucose metabolism (7.26 +/- 0.51 mg.kg-1 FFM.min-1) rose significantly (both P less than 0.05 from matched studies at lower rates of glucose uptake). During all glucose-clamp studies, free fatty acids were comparably suppressed by 40-46% (all P less than 0.005 vs. basal values), whereas fat oxidation was suppressed by 70-80% (all P less than 0.005 vs. basal values). A strong negative correlation was observed between rates of glucose and fat oxidation (r = -0.88, P less than 0.001) when all studies were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of d-fenfluramine on basal glucose turnover and fat-feeding-induced insulin resistance in rats.

There is evidence that fenfluramine improves insulin action independently of its anorectic and weight-loss-inducing properties. Chronic d-fenfluramine also reduces hypothalamic noradrenergic tone, which correlates highly with hepatic glucose output. We report that chronic d-fenfluramine (5 mg.kg-1.day-1) ameliorates insulin resistance induced by high-fat feeding. Insulin action was assessed in adult male rats at basal insulin levels and at hyperinsulinemia (approximately 140 mU/L with the euglycemic clamp technique). Hepatic glucose production, peripheral glucose disposal, and individual tissue glucose metabolism were determined from bolus injections of [3H]-2-deoxyglucose and [14C]glucose. Food intake was matched between groups. Basal glucose turnover was reduced 28% (P less than .05) in fat-fed rats receiving d-fenfluramine (fat + fen). The glucose infusion rate to maintain euglycemia was 22.0 +/- 1.1 mg.kg-1.min-1 in the high-carbohydrate-fed rats, 8.2 +/- 1.0 in fat-fed rats, and 15.1 +/- 0.5 in the fat + fen group. Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 +/- 1.0 to 13.8 +/- 0.6 mg.kg-1.min-1) but was improved by d-fenfluramine (16.9 +/- 0.5, P less than .05 vs. fat fed). Impaired suppression of hepatic glucose output by insulin, caused by fat feeding, was totally reversed by d-fenfluramine. Thus, d-fenfluramine counteracted diet-induced insulin resistance, with the predominant effect on the liver. We hypothesize that d-fenfluramine improves insulin action by reducing hypothalamic noradrenergic tone, which in turn reduces the neural drive to hepatic glucose output and improves the hepatic response to insulin.

The effect of flexible low glycemic index dietary advice versus measured carbohydrate exchange diets on glycemic control in children with type 1 diabetes.

OBJECTIVE: To determine the long-term effect of low glycemic index dietary advice on metabolic control and quality of life in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: Children with type 1 diabetes (n = 104) were recruited to a prospective, stratified, randomized, parallel study to examine the effects of a measured carbohydrate exchange (CHOx) diet versus a more flexible low-glycemic index (GI) dietary regimen on HbA(1c) levels, incidence of hypo- and hyperglycemia, insulin dose, dietary intake, and measures of quality of life over 12 months. RESULTS: At 12 months, children in the low-GI group had significantly better HbA(1c) levels than those in the CHOx group (8.05 +/- 0.95 vs. 8.61 +/- 1.37%, P = 0.05). Rates of excessive hyperglycemia (>15 episodes per month) were significantly lower in the low-GI group (35 vs. 66%, P = 0.006). There were no differences in insulin dose, hypoglycemic episodes, or dietary composition. The low-GI dietary regimen was associated with better quality of life for both children and parents. CONCLUSIONS: Flexible dietary instruction based on the food pyramid with an emphasis of low-GI foods improves HbA(1c) levels without increasing the risk of hypoglycemia and enhances the quality of life in children with diabetes.

Reduced glucose-induced thermogenesis is present in noninsulin-dependent diabetes mellitus without obesity.

Decreased glucose-induced thermogenesis has been observed in all forms of obesity. However, some studies implicate insulin resistance rather than obesity per se as the mechanism by which glucose-induced thermogenesis is reduced. To establish the role of insulin resistance in reduced thermogenesis independent of obesity, we compared energy expenditure in 9 nonobese individuals with noninsulin-dependent diabetes mellitus (NIDDM) to 16 nonobese control subjects using indirect calorimetry and the hyperinsulinemic clamp technique. To document the presence of insulin resistance and reduced glucose-induced thermogenesis in nonobese NIDDM, 6 individuals from each group were studied under identical conditions of hyperinsulinemia (120 mU/m2.min) and euglycemia (approximately 5 mmol/l). Both glucose uptake (0.482 +/- 0.042 vs. 0.737 +/- 0.040 g/min) and energy expenditure above basal (0.04 +/- 0.02 vs. 0.10 +/- 0.02 kcal/min) were decreased in nonobese NIDDM compared to control subjects (both P less than 0.05). To determine whether decreased glucose-induced thermogenesis could be overcome by correcting for reduced glucose uptake, the 9 nonobese NIDDM individuals were age and weight-matched to 9 control subjects and clamps were performed at matched rates of glucose uptake. During a 40 mU/m2.min insulin infusion, the nonobese NIDDM individuals were studied at hyperglycemia (17.5 +/- 1.9 mmol/L) and compared to the control subjects at euglycemia (5.1 +/- 0.1 mmol/L; P less than 0.05). Under these conditions, both groups achieved similar rates of glucose uptake (0.698 +/- 0.040 vs. 0.688 +/- 0.038 g/min, NIDDM and control subjects, respectively) and similar rates of energy expenditure above basal (0.08 +/- 0.03 vs. 0.06 +/- 0.02 kcal/min, P = NS). During 600 mU/m2.min clamps performed at hyperglycemia (19.0 +/- 1.2 vs. 14.5 +/- 1.1 mmol/L, NIDDM vs. control subjects, respectively; P less than 0.05), rates of maximal glucose uptake (1.538 +/- 0.093 vs. 1.518 +/- 0.047 g/min) and energy expenditure above basal (0.34 +/- 0.03 vs. 0.31 +/- 0.03 kcal/min) were also similar (P = NS). In conclusion nonobese NIDDM is associated with both decreased rates of glucose uptake and decreased glucose-induced thermogenesis. Decreased glucose substrate availability, due to impaired insulin action, appears to be the critical determinant of glucose-induced thermogenesis in nonobese NIDDM. These data indicate that decreased thermogenesis in NIDDM is a consequence of insulin resistance and can occur independent of obesity.

Biological determinants of spontaneous physical activity.

A decline in daily physical activity levels is clearly a major factor contributing to the current obesity epidemic affecting both developed and developing countries in the world. This escalating problem is associated with increased morbidity and mortality and reduced psychosocial health. Thus, increasing physical activity has become the strategy of choice in public health strategies to prevent obesity. Efforts to improve levels of physical activity in the population rely upon an accurate understanding of the determinants of physical activity. Most research has focused on environmental and social influences, while the potential for physical activity to be controlled by intrinsic biological processes has been largely overlooked. This review presents some of the compelling and diverse evidence that has emerged recently showing that physical activity energy expenditure is a critical factor in both the successful regulation of energy balance in normal individuals, as well as the abnormal regulation of energy balance that characterizes obesity. Although the metabolic and genetic factors involved in these regulatory processes remain mostly unidentified, some novel discoveries have been made in this area recently and these are described within this review.

Slowly digested and absorbed carbohydrate in traditional bushfoods: a protective factor against diabetes?

The aim of this study was to compare the digestibility and metabolic responses of western foods with traditional staples of two populations that show a susceptibility to diabetes, namely Australian Aborigines and Pacific islanders. Rate of starch digestion was studied in vitro in 37 foods (20 Australian Aboriginal bushfoods, 10 Pacific island foods, and 7 western foods), and rate of absorption of 9 foods (8 bushfoods and 1 western food) was studied in human volunteers. In vitro studies showed that 23 of 30 traditional foods were digested more slowly than 7 western foods. Six of 8 bushfoods produced significantly smaller areas under 3-h postprandial plasma glucose curves than potatoes in seven healthy Caucasian volunteers. There was a good correlation between starch digestibility and plasma glucose response. Our findings are consistent with the hypothesis that carbohydrate in traditional diets is slowly digested and absorbed and may once have been protective against diabetes.

Incomplete absorption of pure fructose in healthy subjects and the facilitating effect of glucose.

Small-intestinal absorption of fructose was investigated in healthy human subjects by sequential breath-hydrogen measurements. Fifty-eight percent of 103 subjects produced greater than 20 microL H2/L after consuming 50 g pure fructose in water. About half of those who absorbed fructose incompletely (incomplete absorbers) had abdominal symptoms. Malabsorption of medium doses of pure fructose may therefore be common in man. When 25 g pure fructose was consumed, only 19% of 21 poor absorbers (of 50 g fructose) still produced excess breath H2. When glucose was taken with fructose, the frequency and amount of excessive breath H2 was substantially reduced. This facilitating phenomenon is not generally known but is important because in natural foods fructose occurs in association or in combination (as sucrose) with glucose. Plasma fructose responses were not lower in poor absorbers presumably because these responses depend more on how much fructose passes through the liver than on how much is absorbed.

Short-term, high-fat diets lower circulating leptin concentrations in rats.

BACKGROUND: Leptin is produced in proportion to body fat mass and can act on the brain to induce satiety and regulate adipose tissue mass; factors other than adipose tissue mass may influence circulating leptin concentrations. OBJECTIVE: We explored the possibility that short-term, moderately high-fat diets induce weight gain by producing inappropriately low circulating leptin concentrations. DESIGN: Female Hooded Wistar rats were fed either a moderately high-fat diet or control diet. Body weight, energy intake, body composition, and fasting plasma leptin were compared after 4 and 14 wk of dietary treatment. RESULTS: After 4 wk, abdominal fat mass was 38% greater in rats fed the high-fat diet than in those fed the control diet (P < 0.01). However, plasma leptin concentrations were 24% lower in animals fed the high-fat diet (P < 0.05), resulting in significantly lower plasma leptin concentrations per unit abdominal fat mass than in control animals (P < 0.005). From 4 to 14 wk, animals fed the high-fat diet gained twice as much weight and consumed 32 kJ/d more than controls (both P < 0.05). At 14 wk, plasma leptin concentrations per unit abdominal fat mass were 27% lower in rats fed the high-fat diet (P = 0.058) and there was a significant negative association between leptin concentrations per unit abdominal fat mass and body weight (r = 0.44, P < 0.05). CONCLUSIONS: In the short term, a moderately high-fat diet is associated with lower than expected circulating leptin concentrations, which correlate with a higher body weight. A high-fat diet may therefore contribute to weight gain by reducing leptin secretion in adipose tissue.

Application of glycemic index to mixed meals.

Plasma glucose and insulin responses to six different meals were determined and compared with values predicted by published glycemic indices of the component foods. The test meals were of different ethnic origins: Indian (lentil curry with rice), Italian (spaghetti bolognaise), Chinese (stir-fried vegetables and chicken with rice), Greek (lentil stew), Western (sirloin chop and vegetables); and Lebanese (sandwich with unleavened bread and hummos). Eight healthy volunteers were given 50 g carbohydrate portions of the above meals after an overnight fast. The glycemic and insulin indices were highest for the Lebanese meal and lowest for the Greek with significant differences among the meals (ANOVA, p less than 0.05). The observed glycemic indices correlated well with the predicted glycemic indices (r = 0.88, p less than 0.01) and insulin responses parallelled the glycemic responses (r = 0.83, p less than 0.05). These results suggest that the glycemic index approach will be useful in planning diets for diabetic people.

Food processing and the glycemic index.

The purpose of the study was to compare the in vitro starch digestibility and postprandial blood glucose response of conventionally-cooked versus factory-processed foods. Carbohydrate portions of three unprocessed foods (boiled rice, sweet corn, and potato) and six processed foods (instant rice, Rice Bubbles, corn chips, Cornflakes, instant potato, and potato crisps) were incubated for 3 h with human saliva and porcine pancreatin. The proportion of starch digested was significantly higher (p less than 0.05) for the processed forms of rice, corn, and potato compared with the respective conventionally cooked foods. In six healthy volunteers who ingested 50 g carbohydrate portions of the above foods the processed foods produced a higher glycemic index (p less than 0.05) in all but one instance. The exception was potato crisps which gave a similar glycemic response to boiled potato.

Glycemic index of processed wheat products.

Our aim was to determine the in vivo glycemic and insulin responses and in vitro starch digestibility of seven processed wheat products (shortbread biscuits, custard, quick-cooking wheat, wholemeal bread, water biscuits, puffed wheat, and puffed crispbread). The degree of starch gelatinization in the foods was measured. Fifty-gram carbohydrate portions of the foods were fed to eight volunteers after an overnight fast. The calculated glycemic indices (GI) (mean +/- SEM) ranged from 43 +/- 10 for custard to 81 +/- 9 for puffed crispbread. Insulin responses paralleled the glycemic responses. The GI correlated positively with the percentage of starch digested in vitro (p less than 0.05). The degree of starch gelatinization ranged from 0.4 to 60% and correlated positively with the percentage starch digested in vitro (p less than 0.05). Differences in the glycemic and insulin responses to wheat products may be explained in part by the extent of processing and the degree of gelatinization achieved.

Plasma glucose and insulin responses to starchy foods in Australian aborigines: a population now at high risk of diabetes.

We compared plasma glucose and insulin responses to an Aboriginal bushfood and its western equivalent in healthy Aborigines and Caucasians. Bush potato (Ipomoea costata), an Aboriginal bushfood which is slowly digested in vitro, and potato (Solanum tuberosum), which has a high glycemic index, were studied. The areas under the glucose and insulin curves for Aborigines were 34% and 42% smaller, respectively, after bush potato than after potato (p less than 0.05). In Caucasians only the insulin response to bush potato was lower (by 19%) than that to potato (p less than 0.05). Compared with Caucasians, Aborigines produced 2.5 times greater glucose and insulin responses to potato (p less than 0.025). Their insulin responses to bush potato were also twice as large (p less than 0.05) although glucose responses were not significantly different. These findings add weight to the hypothesis that rapidly digested carbohydrate in western diets may be one of the factors in the lifestyle change which precipitates diabetes in indigenous populations.

Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats.

Insulin action was assessed by using the hyperinsulinemic (approximately 800 pmol/L) euglycemic clamp in rats fed equal amounts of glucose or fructose (35% of calories) for 4 wk. The glucose infusion rate required to maintain euglycemia was decreased in fructose-fed animals (14.6 +/- 1.4 vs 21.8 +/- 1.1 for glucose-fed rats, p less than 0.001) with this whole-body effect contributed to equally by an impairment in hepatic insulin action and a reduction in peripheral glucose disposal in a range of tissues. There was no difference in basal glucose turnover, energy expenditure, or postprandial blood glucose and insulin responses to the diets. In the fructose-fed rats there was an increase in fasting triglyceride levels by 2 wk. Euglycemic clamp glucose disposal correlated positively and clamp hepatic glucose output correlated negatively with fasting triglyceride levels. In summary, fructose but not glucose feeding led to impaired insulin action in both the liver and peripheral tissues, effects that may depend on antecedent circulating triglyceride levels.

Lipid metabolism in non-insulin-dependent diabetes: effects of long-term treatment with fructose-supplemented mixed meals.

Using fructose in the diabetic diet remains controversial primarily because of the potential for adverse effects on serum lipids. Therefore, lipid metabolism was evaluated in five NIDDM subjects (as inpatients) for 3 mo before and after ingestion of mixed meals containing 13% of calories as fructose. Triglyceride (TG) transport in very-low-density lipoproteins (VLDL) was assessed by multicompartmental analysis of VLDL-TG specific activity after injection of 3H-2-glycerol. There were no deleterious changes in lipid metabolism after fructose supplementation. The fructose diet produced no changes in serial free fatty acids (from 0.39 +/- 0.04 to 0.51 to 0.12 mmol/L), total cholesterol (from 5.43 +/- 0.52 to 5.53 +/- 0.57 mmol/L), high-density lipoproteins (from 0.91 +/- 0.08 to 0.93 +/- 0.08 mmol/L), low-density lipoproteins (from 3.10 +/- 0.52 to 2.92 +/- 0.47 mmol/L), VLDL-TG production (from 2.11 +/- 0.36 to 2.07 +/- 0.30 mmol/h), and fractional catabolic rate (from 0.186 +/- 0.014 to 0.196 +/- 0.03/h). Physiologic amounts of fructose are unlikely to have adverse effects on lipid metabolism when consumed by these diabetic subjects in place of sucrose in mixed meals for a prolonged period.

Novel anti-obesity drugs.

There is increasing evidence that body weight is homeostatically regulated and that in obesity this regulation maintains weight at a high level. Weight loss activates mechanisms that are designed to return individuals to their pre-existing weight. This explains the universally poor results of current strategies to maintain weight loss. On this basis, life-long drug therapy may be justified for those with significant obesity. Currently available drugs include selective serotonin re-uptake inhibitors (e.g., fluoxetine), noradrenergic re-uptake inhibitors (e.g., phentermine), a serotonin and noradrenergic re-uptake inhibitor (sibutramine) and an intestinal lipase inhibitor (orlistat). An active research program is underway to develop new agents based on the rapidly expanding knowledge of the complex mechanisms regulating body weight. Leptin, a hormone produced by adipocytes that inhibits food intake, has undergone clinical trials and analogues are currently being developed. Other agents include amylin, melanocortin-4 receptor agonists, neuropeptide Y antagonists, beta(3) adrenergic agonists and glucagon-like peptide-1 agonists. As some redundancy exists in the central regulatory system controlling body weight, some agents might need to be used in combination to be effective.

Aromatase-deficient (ArKO) mice accumulate excess adipose tissue.

Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.