Acute or long-term energy deficit in lean or obese rodents or humans stimulates food intake or appetite and reduces metabolic rate or energy expenditure. These changes contribute to weight regain in post-obese animals and humans. Some studies show that the reduction in metabolic rate with energy deficit in overweight people is transient. Energy restriction has been shown in some but not all studies to reduce physical activity, and this may represent an additional energy-conserving adaptation. Energy restriction up-regulates expression of the orexigenic neuropeptide Y, agouti related peptide and opioids and down-regulates that of the anorexigenic alpha-melanocyte stimulating hormone or its precursor pro-opioomelanocortin and the co-expressed cocaine and amphetamine-regulated transcript in the arcuate nucleus of the hypothalamus. Recapitulating these hypothalamic changes in sated animals mimics the effects of energy deficit, namely increased food intake, reduced physical activity and reduced metabolic rate, suggesting that these energy-conserving adaptations are at least partially mediated by the hypothalamus.
Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress-induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress-induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6-week restraint, or cold-stress protocol, Npy-null mice exhibit three-fold greater bone loss compared to wild-type mice, owing to suppression of osteoblast activity. This stress-protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin-releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy-null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy-null mice blocks the increase in circulating noradrenaline and the stress-induced bone loss. Thus, NPY protects against excessive stress-induced bone loss, through Y2 receptor-mediated modulation of central and peripheral noradrenergic neurons.
Aims: Energy homeostasis is regulated by a complex interaction of molecules and pathways, and new antiobesity treatments are likely to require multiple pharmacological targeting of anorexigenic or orexigenic pathways to achieve effective loss of excess body weight and adiposity. Cannabinoids, acting via the cannabinoid--1 (CB1) receptor, and neuropeptide Y (NPY) are important modulators of feeding behaviour, energy metabolism and body composition. We investigated the interaction of CB1 and NPY in the regulation of energy homeostasis, hypothesizing that dual blockade of CB1 and NPY signalling will induce greater weight and/or fat loss than that induced by single blockade of either system alone. Methods: We studied the effects of the CB1 antagonist Rimonabant on food intake, body weight, body composition, energy metabolism and bone physiology in wild--type (WT) and NPY knockout (NPY−/−) mice. Rimonabant was administered orally at 10 mg/kg body weight twice per day for 3 weeks. Oral Rimonabant was delivered voluntarily to mice via a novel method enabling studies to be carried out in the absence of gavage--induced stress. Results: Mice with dual blockade of CB1 and NPY signalling (Rimonabant--treated NPY−/− mice) exhibited greater reductions in body weight and adiposity than mice with single blockade of either system alone (Rimonabant--treated WT or vehicle--treated NPY−/− mice). These changes occurred without loss of lean tissue mass or bone mass. Furthermore, Rimonabant--treated NPY−/− mice showed a lower respiratory exchange ratio than that seen in Rimonabant--treated WT or vehicle--treated NPY−/− mice, suggesting that this additive effect of dual blockade of CB1 and NPY involves promotion of lipid oxidation. On the other hand, energy expenditure and physical activity were comparable amongst all treatment groups. Interestingly, Rimonabant similarly and transiently reduced spontaneous and fasting--induced food intake in WT and NPY−/− mice in the first hour after administration only, suggesting independent regulation of feeding by CB1 and NPY signalling. In contrast, Rimonabant increased serum corticosterone levels in WT mice, but this effect was not seen in NPY−/− mice, indicating that NPY signalling may be required for effects of CB1 on the hypothalamo--pituitary--adrenal axis. Conclusions: Dual blockade of CB1 and NPY signalling leads to additive reductions in body weight and adiposity without concomitant loss of lean body mass or bone mass. An additive increase in lipid oxidation in dual CB1 and NPY blockade may contribute to the effect on adiposity. These findings open new avenues for more effective treatment of obesity via dual pharmacological manipulations of the CB1 and NPY systems. INTRODUCTION Obesity, an epidemic disorder and the leading risk factor for type 2 diabetes, results from a prolonged energy imbalance during which intake exceeds expenditure. One of the major obstacles to permanent weight loss in overweight or obese individuals relates to the ability of the body's complex and redundant ...
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