The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.     

Suppression of food intake and body weight gain by naloxone in rats

The effect of acute and chronic administration of naloxone on food acquisition and weight gain in rats was studied in 3 experiments. One injection of a sparingly-soluble salt of naloxone in slow-release vehicle markedly lowered mean food intake over that of control rats injected with the vehicle only. Mean body weight of the naloxone-injected rats was significantly lower than that of the control group for one week.Repeated evening injections (2000 h) of naloxone hydrochloride in saline tended to reduce the night-time feeding below control levels throughout the 10-day period of naloxone administration. Food intake was significantly lower in the 4- and 8-h periods after the first injection of naloxone than that on the preceding saline control night. The initial decreases were offset by increased day-time feeding so that total daily food intake was not significantly altered over the 10 days. When saline was substituted for naloxone, food intake increased.Rats given naloxone following 24 h of fasting consumed significantly less food and gained less weight during 4 h of access to food compared to those receiving saline. After a 48-h fast naloxone-treated rats also gained significantly less body weight than those given saline, but the reduction in food intake was not statistically significant. These results suggest the possibility that endorphins may have a modulating effect on feeding activity.     

Effects of increased energy expenditure on weight gain and adiposity in the LA-corpulent rat

Groups of lean or pre-obese LA/N-cp rats were subjected to a program of vigorous exercise (less than 4 hr/day) or remained sedentary from 6 weeks until 12 weeks of age. Sedentary pre-obese rats gained weight twice as rapidly as sedentary lean rats. Exercise treatment resulted in greater decrements in body wt in obese than in lean rats, but did not result in absolute weight loss in either group. At 12 weeks of age, fat pad weights in principle depots were 10-15 times greater in corpulent than in lean rats and were significantly smaller in the exercised groups of both phenotypes, and corresponded with lower relative adiposity compared to corresponding sedentary groups. Heart weights were greater in corpulent than lean, while gastrocnemius muscle weights were similar in both phenotypes. Exercise was without effect on the weight of either muscle tissue in either phenotype. Interscapular brown adipose tissue weights and the IBAT:BW ratio were greater in obese than in lean rats. IBAT weights were lower in exercised than sedentary rats of either phenotype, but the IBAT:BW ratio was lower only in the obese exercised rats. In sedentary rats, L-alpha-glycerophosphate dehydrogenase and malic enzyme activity were greater in obese than lean, and exercise treatment resulted in increased L-alpha-glycerophosphate dehydrogenase and malic enzyme only in lean rats. These results are consistent with a redistribution of energy expenditure from energy storing to energy dissipating pathways following vigorous exercise, resulting in slowed rates of weight gain and body fat accretion in both lean and obese animals, with the most significant decrements among pre-obese rats.     

Assessment of residual body weight gain and residual intake and body weight gain as feed efficiency traits in the turkey (Meleagris gallopavo)

Background

Since feed represents 70% of the total cost in poultry production systems, an animal’s ability to convert feed is an important trait. In this study, residual feed intake (RFI) and residual body weight gain (RG), and their linear combination into residual feed intake and body weight gain (RIG) were studied to estimate their genetic parameters and analyze the potential differences in feed intake between the top ranked birds based on the criteria for each trait.

Methods

Phenotypic and genetic analyses were completed on 8340 growing tom turkeys that were measured for feed intake and body weight gain over a four-week period from 16 to 20 weeks of age.

Results

The heritabilities of RG and RIG were 0.19 ± 0.03 and 0.23 ± 0.03, respectively. Residual body weight gain had moderate genetic correlations with feed intake (−0.41) and body weight gain (0.43). All three linear combinations to form the RIG traits had genetic correlations ranging from −0.62 to −0.52 with feed intake, and slightly weaker, 0.22 to 0.34, with body weight gain. Sorted into three equal groups (low, medium, high) based on RG, the most efficient group (high) gained 0.62 and 1.70 kg more (P < 0.001) body weight than that of the medium and low groups, yet the feed intake for the high group was less (P < 0.05) than that of the medium group (19.52 vs. 19.75 kg). When separated into similar partitions, the high RIG group (most efficient) had both the lowest (P < 0.001) feed intake (18.86 vs. 19.57 and 20.41 kg) and the highest (P < 0.001) body weight gain (7.41 vs. 7.03 and 6.43 kg) relative to the medium and low groups, respectively.

Conclusions

The difference in feed intake between the top ranked birds based on different residual feed efficiency traits may be small when looking at the average individual, however, when extrapolated to the production level, the lower feed intake values could lead to significant savings in feed costs over time.     

Modification of the caloric intake as a function of energy expenditure in patients with diarrhea]

We have compared, using non protein RQ method, energy expenditures of diarrheic patients with intraperitoneal or intraluminal suppuration and feed enterally (group II) or intravenously (group III). Five non suppurative diarrheic patients feed enterally were studied as control (group I). Carbohydrate, protein and fat intakes were not significantly different in the 3 groups of patients. Patients of group II metabolized significantly less of carbohydrate (p less than 0.01) and more of fat (P less than 0.01) than groups I and III patients. Carbohydrate and fat expenditures of patients of groups I and III were not significantly different. Conclusion: 1) There is a possible trouble of carbohydrate absorption in suppurative diarrheic patients. 2) Therefore caloric intake must be preferably parenteral in these patients.     

Circannual rhythm of food intake in spotted munia and its phase relationship with fattening and reproductive cycles

Summary The tropical spotted munia,Lonchura punctulata, exhibits a pronounced seasonality in reproduction, body weight and food intake. The body weight cycle parallels the reproductive cycle, whereas the food intake cycle is almost in antiphase to it. There is evidence that constant dietary restriction (50% of the maximum intake) causes dissociation of the body weight and reproductive cycles. Because of these relationships we performed experiments on the food intake cycle and its phase relationships with the reproductive and body weight cycles in birds held under constant light. The results indicate persistence of all three cycles. The phase relationships of these three parameters were almost normal, which may indicate that the endogenous oscillators for the cycles of reproduction, body weight and food intake are linked.     

Physical activity and muscle function but not resting energy expenditure impact on weight gain

Understanding whether metabolic factors are predictive of weight gain is important for developing strategies for prevention of weight gain. Recent research has shown that sleeping and resting energy expenditure are not predictive of weight gain. However, exercise endurance, muscular strength, (31)P MRS muscle metabolic economy, and maximum oxygen uptake are independently related to weight gain. Activity-related energy expenditure and the time spent in physical activity are also related to weight gain, with low physical activity explaining approximately 77% of weight gain at 1 year. In addition, weight maintainers spend 80 minutes per day, whereas weight gainers spend less than 20 minutes per day in physical activity equivalent to an intensity of about 4 METS. It is proposed that strength, aerobic fitness, and physical activity are important factors for reducing the rate of weight gain. Although further research is required, these results are suggestive that weight maintenance programs will be more successful if some relatively high-intensity training is included to complement large amounts of low to moderate intense physical activity.     

Energy expenditure and locomotor activity in mice selected for food intake adjusted for body weight

Summary The aim of this study was to examine the differences in physical activity and their contribution to differences in energy utilization in mice, selected either high or low for food intake, adjusted for body weight, which show correlated responses in lean content and metabolic rate. Simultaneous measurements of fasting metabolic rate and activity were made in lines of mice selected at either: a young age, 4-to 6-week food intake corrected for 4-week body weight; or an older age, 8- to 10-week food intake corrected for mean weight at 8 and 10 weeks of age. Correlated response in metabolic rate was found to have been accompanied by changes in locomotor activity near the ages at selection in both sets of lines. Activity, however, accounted for only a small proportion of variation in fasting heat production, generally less than 5%, although a highly positive correlation (r=0.63) between the two traits was found. It was concluded that selection for food intake adjusted for body weight has led to correlated response in physical activity. In consequence, mice selected in the upward direction expend some of the excess energy intake rather than assimilating it as body mass and are, therefore, slightly leaner than their counterparts selected in the downward direction.     

Major gene effect on body mass index: the role of energy intake and energy expenditure

The evidence for a major gene for body mass index (BMI) was investigated using complex segregation analysis (POINTER) in 1691 individuals belonging to 432 nuclear families residing in the Chittoor district of Andhra Pradesh, India. Since the BMI is significantly correlated with energy intake (EI) and energy expenditure of activity (EEA), the effects of each were removed from the BMI using regression analysis, and the segregation analysis was repeated on the energy-adjusted BMI. For BMI, a putative major locus could not be ruled out, and the effect (q = 0.25, accounting for 37% of the phenotypic variance) was remarkably similar to that reported in Western populations. After adjusting the BMI for EI and EEA, however, no evidence in support of a major gene could be observed, suggesting either that EI and EEA mediate the expression of the major gene effect on BMI, or that the same major gene may influence both traits. The pleiotropy hypothesis was further explored using a simple bivariate familial correlation model, in which the significance of familial cross-trait correlations (e.g., BMI in parents with BMI as predicted from the energy variables in the offspring) was examined. The cross-trait resemblance between the two measures was significant for all biological relatives, verifying the presence of shared heritable determinants (i.e., the same gene[s] and/or familial environments) accounting for 58% of the covariation. The significant cross-trait spouse correlations further suggested that at least part of the cross-trait resemblance may be due to shared environmental factors. Therefore, we conclude that there is strong evidence for shared genetic effects between BMI and the energy variables.     

Captopril intake decreases body weight gain via angiotensin-(1-7)

Angiotensin-(1-7) [Ang-(1-7)] plays a beneficial role in cardiovascular physiology by providing a counterbalance to the function of angiotensin II (Ang II). Although Ang II has been shown to be an adipokine secreted by adipocyte and affect lipid metabolism, the role of Ang-(1-7) in adipose tissue remains to be clarified. The aim of the present study was to investigate whether Ang-(1-7) affects lipid metabolism in adipose tissue. Ang-(1-7) increased glycerol release from primary adipocytes in a dose-dependent manner. A lipolytic effect of Ang-(1-7) was attenuated by pretreatment with A-779, a Mas receptor blocker and with an inhibitor of phosphoinositol 3-kinase (PI3K), or eNOS. However, losartan and PD123319 did not cause any change in Ang-(1-7)-induced lipolysis. Ang-(1-7)-induced lipolysis had an addictive effect with isoproterenol. In normal rats, chronic intake of captopril for 4 wks decreased body weight gain and the amount of adipose tissue and increased plasma Ang-(1-7) level. These effects were attenuated by administration of A-779. The levels of Mas receptor and phosphorylation of hormone-sensitive lipase (p-HSL) were significantly increased by treatment with captopril and these captopril-mediated effects were attenuated by the administration of A-779. There was no difference in diameter of adipocytes among sham, captopril- and captopril+A-779-treated groups. The similar effects of captopril on body weight, expression of Mas receptor, and p-HSL were observed in Ang-(1-7)-treated rats. These results suggest that captopril intake decreased body weight gain partly through Ang-(1-7)/Mas receptor/PI3K pathway.     

Voglibose administration regulates body weight and energy intake in high fat-induced obese mice

We tested whether long-term administration of voglibose (VO) prevents diet induced obesity in addition to hypoglycemic effects in high fat fed mice and further investigated the underlying mechanisms by which voglibose exerts its weight lowering effect. Male C57BL/6 mice were fed ad libitum for 12 weeks with the control diet (CTL), high-fat diet (HFD) or the HFD with VO supplementations. Blood lipid profile, plasma leptin levels and hepatic triglyceride content, as well as expressions of genes involved in appetite and mitochondrial function were examined. The results showed that VO significantly reduced body weight, fat mass and energy intakes in high fat fed mice. VO showed improved metabolic profiles including blood glucose, triglyceride and free fatty acid. Elevated levels of plasma leptin in HFD were significantly reduced with the VO, furthermore, VO modulated the hypothalamic expressions of leptin receptors and appetite related genes. VO showed the upregulated expressions of PGC-1 in the liver and epididymal adipose tissue. In conclusion, VO may exert antiobesity properties through reductions in energy intake and improvement in mitochondrial function, indicating that VO has potential therapeutic use in patients with obesity, type 2 diabetes, and related complications.     

Restriction of energy intake, energy expenditure, and aging

Energy restriction (ER), without malnutrition, increases maximum life span and retards the development of a broad array of pathophysiological changes in laboratory rodents. The mechanism responsible for the retardation of aging by ER is, however, unknown. One proposed explanation is a reduction in energy expenditure (EE). Reduced EE may increase life span by decreasing the number of oxygen molecules interacting with mitochondria, thereby lowering reactive oxygen species (ROS) production. As a step toward testing this hypothesis, it is important to determine the effect of ER on EE. Several whole-body, organ, and cellular studies have measured the influence of ER on EE. In general, whole-body studies have reported an acute decrease in mass-adjusted EE that disappears with long-term ER. Organ-specific studies have shown that decreases in EE of liver and gastrointestinal tract are primarily responsible for initial reductions in EE with ER. These data, however, do not determine whether cellular EE is altered with ER. Three major processes contributing to resting EE at the cellular level are mitochondrial proton leak, Na(+)-K(+)-ATPase activity, and protein turnover. Studies suggest that proton leak and Na(+)-K(+)-ATPase activity are decreased with ER, whereas protein turnover is either unchanged or slightly increased with ER. Thus, two of the three major processes contributing to resting EE at the cellular level may be decreased with ER. Although additional cellular measurements are needed, the current results suggest that a lowering of EE could be a mechanism for the action of ER.