Neuroscience
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Selected neurons of the hypothalamus are equipped with molecules specialized in sensing the energy status of the organism. Upon activation or inhibition by central and systemic factors, such as neurotransmitters, hormones, cytokines, and nutrients, these molecules play important roles in the regulation of neuronal responses that control whole-body energy homeostasis. Dietary fats can control hypothalamic function by acting upon distinct energy sensing systems. ⋯ In addition, recent studies have identified lipid-sensing G-protein-coupled receptors in the hypothalamus, revealing their involvement in the regulation of caloric intake and energy expenditure, as well as in the hypothalamic inflammatory response that occurs in obesity. Because of advances in the generation of synthetic ligands for this class of receptors, it is expected that pharmacological modulation of selected lipid-sensing G-protein-coupled receptors in the central nervous system could provide therapeutic advances in obesity and other metabolic diseases. Here we review seminal work in this field.
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In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. ⋯ Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.
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Spexin (SPX) is a novel satiety factor that putatively binds the galanin receptors R2 and R3 (GalR2/R3). SPX reduces body weight, and circulating SPX is decreased in obesity. It is unknown how SPX and its receptors are regulated in the hypothalamus, critical for energy homeostasis. ⋯ We also describe the presence of OCT-1 and C/EBP-β response elements in the 5' regulatory region of Spx and demonstrate that SNP increases binding of C/EBP-β to this region, but not Oct-1 mRNA nor OCT-1 binding. Our findings suggest an acute modulation of anorexigenic SPX signaling by palmitate and NO. Furthermore, ER stress and C/EBP-β appear to mediate the changes in Spx, GalR2 and GalR3 in hypothalamic neurons.
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Amylin is a pancreatic peptide, which acts as a key controller of food intake and energy balance and predominately binds to three receptors (AMY 1-3). AMY 1-3 are composed of a calcitonin core receptor (CTR) and associated receptor-activity modifying proteins (RAMPs) 1-3. Using RAMP1, RAMP3 and RAMP1/3 global KO mice, this study aimed to determine whether the absence of one or two RAMP subunits affects food intake, glucose homeostasis and metabolism. ⋯ While female mice generally weighed less than male mice, only RAMP1 KO showed a clear sex difference in meal pattern and food intake tests. Lastly, a decrease in CTR fibers did not consistently correlate with a decrease in amylin- induced c-Fos expression in the area postrema (AP). Ultimately, the results from this study provide evidence for a role of RAMP1 in mediation of fat utilization and a role for RAMP3 in glucose homeostasis and amylin's anorectic effect.
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The preclinical multicomponent free-choice high-fat high-sucrose (fcHFHS) diet has strong validity to model diet-induced obesity (DIO) and associated maladaptive molecular changes in the central nervous system. fcHFHS-induced obese rats demonstrate increased sensitivity to intracerebroventricular infusion of the orexigenic Neuropeptide Y (NPY). The brain region-specific effects of NPY signaling on fcHFHS diet component selection are not completely understood. For example, fcHFHS-fed rats have increased intake of chow and fat following intracerebroventricular NPY infusion, whereas NPY administration in the nucleus accumbens, a key hub of the reward circuitry, specifically increases fat intake. ⋯ This effect was mediated specifically by chow intake in fcHFHS-fed rats. The orexigenic effects of intra-LHA NPY were prevented by NPY1R and NPY5R antagonism in chow-fed rats, but only by NPY5R antagonism in fcHFHS-fed rats. Thus, NPY signaling has brain region-specific effects on fcHFHS component selection and LHA NPYR sensitivity is dysregulated during consumption of a fcHFHS diet.