Using pharmacological tools, a role for opioid receptors in the regulation of food intake has been documented. However, the involvement of specific receptor subtypes remains questionable, and little information is available regarding a role for opioid receptors in energy metabolism. Using adult male mice lacking the -opioid receptor (MOR) gene (MOR ؊/؊ ), we show that the MOR is not essential for the maintenance of normal levels of ad libitum food intake but does modulate the efficiency of energy storage during high-fat diets through the regulation of energy partitioning. When fed a regular diet, MOR ؊/؊ mice displayed only subtle alterations in energy homeostasis, suggesting a relative overuse of fat as a fuel source in the fed state. When fed a high-fat diet, MOR ؊/؊ mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice. This resistance to obesity was associated with a strong induction of the expression of key mitochondrial enzymes involved in fatty acid oxidation within skeletal muscle. This metabolic role of the MOR, which is consistent with the properties of a "thrifty gene," suggests that the MOR pathway is a potential target for pharmacological intervention in the treatment of obesity associated with the intake of fatty diets. Diabetes 54: 3510 -3516, 2005 T he endogenous opioid system encompasses cloned receptor populations (, ␦, and ) and ligands (␤-endorphin, the enkephalins, and the dynorphins). Extensive work indicates that the opioid system plays a role in the regulation of appetite. Opioid receptors and peptides are expressed in sites of the central nervous system that play a role in regulating feeding behavior, and pharmacological experiments using opioid receptor ligands show that agonists promote eating and antagonists decrease food intake, at least in the short term (1-3). Numerous pharmacological studies indicate that opioids also play a role in modulating the rewarding effects of food (3-5). In contrast, little information suggests that opioids have a role in energy metabolism (6 -8).The need to establish the specific role of the opioid receptors in energy homeostasis has led to studies using putative specific opioid receptor ligands or, more recently, antisense probes directed against specific exons of opioid receptor genes (3,9). Pharmacological studies suggest that the and pathways are part of an interconnected brain network and participate in the orexigenic effect of several peptides that regulate food intake (10 -13). However, the interpretation of these data is complicated by our poor knowledge of the in vivo selectivity of ligand-receptor interactions that have been established in vitro (9,14).Recent studies conducted in mutant mice null for the opioid receptors have complemented pharmacological approaches and clarified the role of each receptor in nociception, anxiety, and drug abuse (14). To further define the role of the -opioid receptor (MOR) pathway in energy homeostasis, we characterized mice lacking the MOR gene ...

No abstract

With one billion people overweight worldwide, the need to identify risk factors and treatments for obesity is urgent. The present study determined whether rats genetically prone to diet-induced obesity (DIO) show preexisting differences in meal microstructure and are sensitive to central anorectic effects of corticotropin-releasing factor type 2 (CRF 2 ) receptor stimulation. Male, selectively bred DIO rats and their diet resistant (DR) counterparts (n = 9/genotype) were weaned onto low-fat chow and compared as young adults for spontaneous or intracerebroventricular urocortin 2 administration-induced (0, 0.3, 1, 3 μg) differences in ingestion. DIO rats were hyperphagic selectively at the dark cycle onset, showing shorter latencies to initiate feeding, faster returns to eating following meal completion, and a lower satiety ratio than DR rats. At other times, DIO rats had briefer postmeal intervals, but ate smaller and briefer meals, resulting in normal intake. DIO rats also ate faster than DR rats. Urocortin 2 was less potent in DIO rats, ineffective at the 0.3 μg dose, but produced CRF 2 antagonist-reversible anorexia at higher doses. Though heavier, chow-maintained DIO rats were proportionately as or more lean than DR rats. Thus, DIO rats showed signs of a preexisting, heritable deficit in the maintenance of postmeal satiety and a reduced sensitivity to anorectic CRF 2 agonist stimulation. The meal patterns of DIO rats temporally resemble human 'snacking' behaviour, which predicts adult obesity. Because central CRF 2 stimulation retains full anorectic efficacy at higher doses in the DIO model, manipulating this neuropeptidergic system might yield new therapeutic approaches for diet-induced obesity.

Patients with anorexia nervosa have been shown previously to display distortions in body image perception. Bruch has postulated that these disturbances as well as disturbances in interoception are meaningfully related to the development of the syndrome. We hypothesized that disturbances in body image, as measured by a distorting photograph technique, and interoception, as measured by a satiety-aversion to sucrose test, should be demonstrable in anorexic patients vs. normal controls. Furthermore, these disturbances should be modifiable by external cues (looking at one's image in a mirror and ingesting isocaloric "high" and "low" calorie connotation meals). We also hypothesized that body image and interoceptive disturbances would be interrelated in the same individuals. Results indicated that patients with anorexia nervosa (N = 26) differed from normal controls (N = 16) in overestimating their body sizes (p = 0.06) and in failing to develop an aversion to the sucrose tastes (p less than 0.001). However, neither viewing one's image in a mirror nor ingesting both "high and "low" calorie connotation meals altered body size perception. Intrasubject body size estimates were very stable from week to week for the anorexic subjects (r = +0.75, p less than 0.001) but less for the controls (r = +0.45, p less than 0.05). The data revealed that overestimation of body size was closely related to the failure to develop an aversion to sucrose tastes in anorexic patients.