• Energy Research

The results of short-term studies in humans suggest that, compared with glucose, acute consumption of fructose leads to increased postprandial energy expenditure and carbohydrate oxidation and decreased postprandial fat oxidation. The objective of this study was to determine the potential effects of increased fructose consumption compared with isocaloric glucose consumption on substrate utilization and energy expenditure following sustained consumption and under energy-balanced conditions.As part of a parallel arm study, overweight/obese male and female subjects, 40-72 years, consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Energy expenditure and substrate utilization were assessed using indirect calorimetry at baseline and during the 10th week of intervention.Consumption of fructose, but not glucose, led to significant decreases of net postprandial fat oxidation and significant increases of net postprandial carbohydrate oxidation (P<0.0001 for both). Resting energy expenditure (REE) decreased significantly from baseline values in subjects consuming fructose (P=0.031) but not in those consuming glucose.Increased consumption of fructose for 10 weeks leads to marked changes of postprandial substrate utilization including a significant reduction of net fat oxidation. In addition, we report that REE is reduced compared with baseline values in subjects consuming fructose-sweetened beverages for 10 weeks.

Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weight-reducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat diet-induced obesity.

Despite compelling evidence that oxytocin (OT) is effective in reducing body weight (BW) in diet-induced obese (DIO) rodents, studies of the effects of OT in humans and rhesus monkeys have primarily focused on noningestive behaviors. The goal of this study was to translate findings in DIO rodents to a preclinical translational model of DIO. We tested the hypothesis that increased OT signaling would reduce BW in DIO rhesus monkeys by inhibiting food intake and increasing energy expenditure (EE). Male DIO rhesus monkeys from the California National Primate Research Center were adapted to a 12-h fast and maintained on chow and a daily 15% fructose-sweetened beverage. Monkeys received 2× daily subcutaneous vehicle injections over 1 wk. We subsequently identified doses of OT (0.2 and 0.4 mg/kg) that reduced food intake and BW in the absence of nausea or diarrhea. Chronic administration of OT for 4 wk (0.2 mg/kg for 2 wk; 0.4 mg/kg for 2 wk) reduced BW relative to vehicle by 3.3 ± 0.4% (≈0.6 kg; P < 0.05). Moreover, the low dose of OT suppressed 12-h chow intake by 26 ± 7% ( P < 0.05). The higher dose of OT reduced 12-h chow intake by 27 ± 5% ( P < 0.05) and 8-h fructose-sweetened beverage intake by 18 ± 8% ( P < 0.05). OT increased EE during the dark cycle by 14 ± 3% ( P < 0.05) and was associated with elevations of free fatty acids and glycerol and reductions in triglycerides suggesting increased lipolysis. Together, these data suggest that OT reduces BW in DIO rhesus monkeys through decreased food intake as well as increased EE and lipolysis.

Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor α, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based onin vitrostudies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24 h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity.

AbstractObjective: The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose.Research Methods and Procedures: We compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice.Results: Exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern.Discussion: These data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

Decreased ventromedial hypothalamic (VMH) serotonergic activity occurs in genetic and diet-induced animal models of obesity. We previously found that this activity was lower in adult and in 12-day-old Zucker fa/ favs. Fa/ Fapups, the fa/ faanimals being identified by their greater adiposity. In the present study, we evaluated fa/ farats (Brown Norway-Zucker hybrids) at ages 2, 4, 7, and 12 days to test the hypothesis that lower VMH serotonergic activity occurs before increased adiposity and/or attenuated energy expenditure. Our results negate this hypothesis. VMH serotonergic activity showed no consistent genotype differences even at 12 days of age. In contrast, by day 7, fa/ favs. Fa/ Fapups had higher serum leptin concentrations, greater percent body fat, lower resting and cold-induced energy expenditure, and lower activity of brown fat thyroxine 5′-deiodinase, an enzyme that converts thyroxine to triiodothyronine. We conclude that the onset of increased adiposity induced by the fa gene does not require decreased VMH serotonergic activity and that the lower serotonergic activity seen in older fa/ fapups may be secondary to metabolic consequences of the disruption of the leptin regulatory pathway.

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm. Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.