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Resumen La obesidad y el sobrepeso son problemas de origen multifactorial, la interacción de los factores ambientales, genéticos y conductuales parecen ser la clave en el desarrollo de esta patología. Los receptores MC3 (rMC3) y MC4 (rMC4), participan en la regulación del balance energético (consumo de alimento, gasto energético y peso corporal), su mutación genética está asociada con el incremento de la adiposidad y el desarrollo de la obesidad. El conocimiento que se tiene de estos receptores y su función aún es limitado, principalmente con respecto a los rMC3 y, aunque los rMC4 se están posicionando como un blanco terapéutico potencial para el tratamiento de la obesidad, se requiere de mayor investigación clínica. Por lo tanto, el propósito de este documento es presentar evidencia de la participación de los receptores MC3 y MC4 en el desarrollo de la obesidad, a través de los resultados encontrados en algunas investigaciones, tanto en modelos animales como en humanos.
Abstract Obesity and overweight are problems of multifactorial origin, the interaction of environmental, genetic, and behavioral factors seems to be the key in the development of this pathology. The MC3 (rMC3) and MC4 (rMC4) receptors participate in the regulation of energy balance (food intake, energy expenditure and body weight), their genetic mutation is associated with increased adiposity and the development of obesity. Knowledge of these receptors and their function is still limited, mainly with respect to rMC3 and, although rMC4 are positioning themselves as a potential therapeutic target for the treatment of obesity, further clinical research is required. Therefore, the purpose of this document is to present the participation of MC3 and MC4 receptors in the development of obesity, through the results found in some investigations, both in animal and in human´s models.
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Objective To study the effect of intracerebroventricular injection of leptin on proopiomelanocortin(POMC) and neuropeptide Agouti related protein (AGRP) and fasting blood glucose (FBG) in rats with type 2 diabetes mellitus (T2DM).Methods Eighty male 8-week-age SD rats with T2DM were selected and divided into two groups:intracerebroventricular injection of leptin group(n=40)and intracerebroventricular injection of vehicle control group(n =40).Intracerebroventricular injection of 5 μL/kg(fasting leptin level 15 ng/mL) leptin was performed in the leptin injection group,and the control group was injected with same amount of vehicle instead.After 48 h,the FBG level was determined,and the levels of POMC and AGRP were detected by the titer method.Results The level of FBG in the leptin injection group was significantly lower than that in the control group(P＜ 0.05),the expression of serum POMC in the leptin injection group was significantly higher than that in control group(P＜0.05),The expression of AGRP in the leptin injection group was significantly decreased than control group(P＜0.05).Conclusion intracerebroventricular injection of leptin can significantly reduce the FBG level in rats with T2DM,increases POMC expression and decreases AGRP associated protein expression.
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Objective To investigate the effect of nesfatin-1 (NSF-1) on T-type Ca2+ channel currents in adult mouse dorsal root ganglion (DRG) neurons and possible signal transduction mechanisms involved.Methods We measured the expression of melanocortin 4 receptors(MC4-R)in mouse DRG by using western blotting analysis.The whole-cell patch clamp technique was used to record the effects of NSF 1 on T-type Ca2+ channel currents in small DRG neurons and several ligands were experimented to further clarify relevant signaling pathways.Results MC4-Rs were abundantly expressed in DRG neurons.NSF-1 enhanced T-type calcium channel currents in a dose-dependent manner in small DRG neurons in mice.NSF-1 mediated increment of T-type calcium channel currents was blocked by the MC4-R antagonist HS024,phosphokinase C antagonists GF109203X,and chelerythrine chloride,while the blockade of phospohokinase A PKI 6-22 elicited no such effects.Conclusions NSF-1 can enhance T type calcium channel currents in small DRG neurons through an MC4-R-dependent PKC signaling pathway.
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Obesity is a multifactorial disease that is rarely associated to single gene defects. However, due to their direct cause-effect relationships, those genetic defects that cause some forms of monogenic obesity are relevant in the study of mechanisms that contribute to increased energy intake and body fat accumulation. Most of the genes that have been shown to cause monogenic obesity are related to the leptin-melanocortin system. The functionality of this system has been elucidated through natural mutations (Agouti, ob and db) in mice and knock-out models. Mutations related to human monogenic obesity have been described in leptin, leptin receptor, proopiomelanocortin, prohormone convertase 1 or melanocortin receptor 4 genes. Therapy with human recombinant leptin in patients with genetic deficiency of the hormone is an effective medical treatment of obesity, although only applicable to very few families. The use of leptin-melanocortin agonists, drugs to avoid leptin resistance or combinations of treatments with leptin and other satiating peptides are currently being investigated for multifacotiral human obesity (Rev Méd Chile 2009; 137:1225-34).