Obesidade genética não sindrômica: histórico, fisiopatologia e principais genes / Non-syndromic genetic obesity: history, pathophysiology and key genes

A obesidade é definida pelo excesso de gordura corporal acumulada no tecido adiposo quando o indivíduo atinge valores de IMC igual ou superior a 30 Kg/m2. Constitui um dos principais fatores de risco para várias doenças não transmissíveis (DNTs) como por exemplo, diabetes mellitus tipo 2 (DM2), doenças cardiovasculares, hipertensão arterial, acidente vascular cerebral e até mesmo o câncer. Embora a obesidade esteja diretamente relacionada com o consumo calórico excessivo em relação ao gasto energético diário, sua etiologia pode estar associada aos baixos níveis de atividade física, às alterações neuroendócrinas e aos fatores genéticos. Considerando o componente genético, esta pode ser classificada como sindrômicas e estar associada às alterações cromossômicas estruturais ou numéricas, ou como não sindrômica, quando relacionada, principalmente, com os polimorfismos de nucleotídeos simples (SNPs) em alelos que atuam como herança monogênica, ou ainda com a interação vários genes (poligênica multifatorial). Apesar de existirem muitas etiologias diferentes, normalmente a obesidade é tratada a partir da mesma abordagem, desconsiderando a fisiologia que a desencadeou. Dessa forma, o objetivo do presente trabalho foi abordar a obesidade genética não sindrômica por meio a) da descrição breve de perspectiva histórica sobre seu entendimento; b) da exposição dos principais mecanismos moleculares envolvidos com o controle de peso; c) da compilação dos principais genes e SNPs relacionados; d) da definição dos principais genes; e e) da abordagem das principais perspectivas de intervenção.

Obesity is defined as excess body fat accumulated in the adipose tissue when the individual reaches BMI values equal to or greater than 30 kg/m2. It is one of the main risk factors for several non-communicable diseases (NCDs), such as Type 2 Diabetes mellitus (T2D), cardiovascular diseases, high blood pressure, stroke and even cancer. Although obesity is directly related to excessive calorie intake in relation to daily energy expenditure, its etiology may be associated with low levels of physical activity, neuroendocrine changes, and genetic factors. Considering the genetic component, it can be classified as syndromic and be associated with chromosomal or numerical changes, or as non-syndromic and being related mainly to single nucleotide polymorphisms (SNPs) in alleles that act as monogenic inheritance, or with an interaction of several genes (multifactorial polygenic). Although there are many different etiologies, obesity is usually treated using the same approach, disregarding the physiology that triggered it. Thus, the aim of this study was to address non-syndromic genetic obesity through a) a brief description of a historical perspective on its understanding; b) the exposure of the main molecular mechanisms involved in weight control, c) the compilation of the key genes and related SNPs, d) the definition of the key genes and e) the approach of the main intervention representations.

Disfunção hipotalâmica na obesidade / Hypothalamic dysfunction in obesity

A obesidade, definida como o acúmulo excessivo ou anormal de gordura que pode causar dano à saúde do indivíduo, é considerada atualmente um dos principais problemas de saúde pública. Resulta de um desequilíbrio entre a ingestão alimentar e o gasto corporal de energia. O controle do balanço energético de animais e seres humanos é realizado pelo sistema nervoso central (SNC) por meio de conexões neuroendócrinas, em que hormônios periféricos circulantes, como a leptina e a insulina, sinalizam neurônios especializados do hipotálamo sobre os estoques de gordura do organismo e induzem respostas apropriadas para a manutenção da estabilidade desses estoques. A maioria dos casos de obesidade se associa a um quadro de resistência central à ação da leptina e da insulina. Em animais de experimentação, a dieta hiperlipídica é capaz de induzir um processo inflamatório no hipotálamo, que interfere com as vias intracelulares de sinalização por esses hormônios, resultando em hiperfagia, diminuição do gasto de energia e, por fim, obesidade. Evidências recentes obtidas por intermédio de estudos de neuroimagem e avaliação de marcadores inflamatórios no líquido cefalorraquidiano de indivíduos obesos sugerem que alterações semelhantes podem estar presentes também em seres humanos. Nesta revisão, apresentamos sumariamente os mecanismos envolvidos com a perda do controle homeostático do balanço energético em modelos animais de obesidade e as evidências atuais de disfunção hipotalâmica em humanos obesos.

Obesity, defined as abnormal or excessive fat accumulation that may impair life quality, is one of the major public health problems worldwide. It results from an imbalance between food intake and energy expenditure. The control of energy balance in animals and humans is performed by the central nervous system (CNS) by means of neuroendocrine connections, in which circulating peripheral hormones, such as leptin and insulin, provide signals to specialized neurons of the hypothalamus reflecting body fat stores, and induce appropriate responses to maintain the stability of these stores. The majority of obesity cases are associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways, and results in hyperphagia, decreased energy expenditure and, ultimately, obesity. Recent evidence obtained from neuroimaging studies and assessment of inflammatory markers in the cerebrospinal fluid of obese subjects suggests that similar alterations may be also present in humans. In this review, we briefly present the mechanisms involved with the loss of homeostatic control of energy balance in animal models of obesity, and the current evidence of hypothalamic dysfunction in obese humans.

Effects of reversible inactivation of the dorsomedial hypothalamus on panic- and anxiety-related responses in rats

The medial hypothalamus is part of a neurobiological substrate controlling defensive behavior. It has been shown that a hypothalamic nucleus, the dorsomedial hypothalamus (DMH), is involved in the regulation of escape, a defensive behavior related to panic attacks. The role played by the DMH in the organization of conditioned fear responses, however, is less clear. In the present study, we investigated the effects of reversible inactivation of the DMH with the GABA A agonist muscimol on inhibitory avoidance acquisition and escape expression by male Wistar rats (approximately 280 g in weight) tested in the elevated T-maze (ETM). In the ETM, inhibitory avoidance, a conditioned defensive response, has been associated with generalized anxiety disorder. Results showed that intra-DMH administration of the GABA A receptor agonist muscimol inhibited escape performance, suggesting an antipanic-like effect (P < 0.05), without changing inhibitory avoidance acquisition. Although a higher dose of muscimol (1.0 nmol/0.2 µL; N = 7) also altered locomotor activity in an open field when compared to control animals (0.2 µL saline; N = 13) (P < 0.05), the lower dose (0.5 nmol/0.2 µL; N = 12) of muscimol did not cause any motor impairment. These data corroborate previous evidence suggesting that the DMH is specifically involved in the modulation of escape. Dysfunction of this regulatory mechanism may be relevant in the genesis/maintenance of panic disorder.

[Effect of vibration stress on the sexually dimorphic nucleus [SDN] of hypothalamus of immature male wistar rat]

The sexually dimorphic nuclei in the preoptic area [SDN-POA] of hypothalamus are a cluster of cells which size, shape and their cellular morphology are related to gender and age. Different stressors affect on hypothalamus nuclei. In this study, effect of vibration stress was studied on endocrine system and sexually dimorphic nucleus [SDN] of hypothalamus. In this experimental study, male immature Wistar rats [15 days old] were divided into 3 groups Control, Experimental E350 and E500. Experimental groups were exposed to vibration stress by shaker with frequency 350mot/min and 500mot/min, 15 minutes daily for 3 weeks. At the end of this period, serum plasmic hormones, such as cortisol, testosterone, estradiol and progesterone, were evaluated. Sections of the brain tissue were prepared for histological and microscopic studies. Cortisol levels increased significantly in experimental E350 [p<0.05] and E500 [p<0.001] groups. Testosterone level decreased significantly in experimental E500 [p<0.01] group. Progesterone increased significantly in experimental E500 [p<0.01]. Estradiol did not show a significant decrease. Microscopic studies of brain showed significant decrease of number and density of sexually dimorphic nuclei in the preoptic area [SDN-POA] of hypothalamus in male immature Wistar rats with vibration stress. Vibration stress induces dysfunction of hypothalamus-pituitary-adrenal axis which can lead to homosexuality and other sexually behavioral disorders

[Comparing the SSR changes in patients with depression, mania and healthy persons]

Skin sympathetic response [SSR] is an electrophysiological techniques and a central polysynaptic process. In mood disorders there are some changes in the cortex, hypothalamus activity, limbic system and basalganglia. Therefore, we compare the SSR changes in the patients with depression, mania and healthy persons. The patients with depression and mania were chosen based on DSM IV criterion by the psychiatrist. In cross-sectional analytic study, control group was selcted away healthy men and women. The SSR was written by physiograph. The stimulat electrod was fixed on the middle finger of the left hand and 5 sympathetic responses were recored for every sample. The mean of amplitude, duration and latency time were computed and compared among three groups. The mean of latency in control, mania and depressed groups were not statistically difference [p=.8]. There were no difference between mean of duration in latency time in three groups. The mean of amplitude were not significant in three groups. It seems hypothalamus has not direct effect balance of sympathy skin responses

Alteraciones en el eje hipotálamo-tejido adiposo y su relación con el riesgo para la aterosclerosis coronaria / Alterations in hypothalamus-adipose tissue axis in relation with the risk of coronary atherosclerosis

Recent population studies in Southern Argentina have found a sharp rise in prevalence of overweight and obesity in both sexes and specially after fifty years of age. Hence, the obesity in itself was found associated with the presence of metabolic syndrome (MS) and coronary heart disease, which have been demonstrated by angiography studies. The regulation of energy homeostasis is controlled by interactions between the central nervous system (neurotransmitters and neuropeptides) and the peripheric system (hormones) through very complex mechanisms. Genetics or acquired alterations in these regulation systems can be the origin of obesity and specially of central obesity. The visceral adipose tissue can be considered a secretor organ and its mass increment could generate insulin-resistance (IR) state, which directly or indirectly, could develop into endothelial dysfunction and coronary atherosclerosis. Although some studies estimate that 40% of IR are of genetic origin, a high proportion of these are acquired by inadequate habits in life style (specially excess of food intake and low physical activity). Finally, a better knowledge of the central and peripheric regulations in alimentation habits and energetic balance could help to develop treatments to decrease the incidence of these metabolic alterations and, consequently the morbidity and mortality due to coronary atherosclerosis.

Estudios poblacionales en la región sur de Argentina mostraron una elevada prevalencia de sobrepeso y obesidad en sujetos de ambos sexos, sobre todo luego de los 50 años de edad; laobesidad central se halló fuertemente asociada con la presencia del síndrome metabólico (SM) y con la enfermedadcoronaria demostrada por angiografía. La regulación de la homeostasis de la energía se realiza a travésde la interacción entre el sistema nervioso central (neurotransmisores y neuropéptidos) y el sistema periférico(hormonas) mediante complejos mecanismos. Alteraciones genéticas o adquiridas en estos sistemas deregulación pueden conducir a la obesidad y en especial a la obesidad central. Considerando al tejido adiposovisceral como un órgano secretor, incrementos de su masa pueden generar estados de insulino-resistencia (IR),la cual directa o indirectamente puede conducir a la disfunción endotelial y a la aterosclerosis coronaria. Aunqueun 40% de IR serían de origen genético, una elevada proporción de ellos son adquiridos por conductasinadecuadas en el estilo de vida (exceso de ingesta de calorías y baja actividad física). Un mayor conocimientode la regulación central y periférica de los hábitos alimentarios y del balance energético podría ayudar a desarrollartratamientos para disminuir la incidencia de estas alteraciones metabólicas y con ello la probabilidad deenfermar o morir por enfermedad coronaria.

The neuroimmune-endocrine axis: pathophysiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics

Cytokines are molecules that were initially discovered in the immune system as mediators of communication between various types of immune cells. However, it soon became evident that cytokines exert profound effects on key functions of the central nervous system, such as food intake, fever, neuroendocrine regulation, long-term potentiation, and behavior. In the 80's and 90's our group and others discovered that the genes encoding various cytokines and their receptors are expressed in vascular, glial, and neuronal structures of the adult brain. Most cytokines act through cell surface receptors that have one transmembrane domain and which transduce a signal through the JAK/STAT pathway. Of particular physiological and pathophysiological relevance is the fact that cytokines are potent regulators of hypothalamic neuropeptidergic systems that maintain neuroendocrine homeostasis and which regulate the body's response to stress. The mechanisms by which cytokine signaling affects the function of stress-related neuroendocrine systems are reviewed in this article.