Radiologic evidence that hypothalamic gliosis is improved after bariatric surgery in obese women with type 2 diabetes.

BACKGROUND/OBJECTIVES: Hypothalamic neurons play a major role in the control of body mass. Obese subjects present radiologic signs of gliosis in the hypothalamus, which may reflect the damage or loss of neurons involved in whole-body energy homeostasis. It is currently unknown if hypothalamic gliosis (1) differs between obese nondiabetic (ND) and obese diabetic subjects (T2D) or (2) is modified by extensive body mass reduction via Roux-n-Y gastric bypass (RYGB). SUBJECTS/METHODS: Fifty-five subjects (all female) including lean controls (CT; n = 13), ND (n = 28), and T2D (n = 14) completed at least one study visit. Subjects underwent anthropometrics and a multi-echo MRI sequence to measure mean bilateral T2 relaxation time in the mediobasal hypothalamus (MBH) and two reference regions (amygdala and putamen). The obese groups underwent RYGB and were re-evaluated 9 months later. Analyses were by linear mixed models. RESULTS: Analyses of T2 relaxation time at baseline showed a group by region interaction only in the MBH (P < 0.0001). T2D had longer T2 relaxation times compared to either CT or ND groups. To examine the effects of RYGB on hypothalamic gliosis a three-way (group by region by time) mixed effects model adjusted for age was executed. Group by region (P < 0.0001) and region by time (P = 0.0005) interactions were significant. There was a reduction in MBH relaxation time by RYGB, and, although the T2D group still had higher T2 relaxation time overall compared to the ND group, the T2D group had significantly lower T2 relaxation time after surgery and the ND group showed a trend. The degree of reduction in MBH T2 relaxation time by RYGB was unrelated to clinical outcomes. CONCLUSION: T2 relaxation times, a marker of hypothalamic gliosis, are higher in obese women with T2D and are reduced by RYGB-induced weight loss.

Effect of pioglitazone treatment on brown adipose tissue volume and activity and hypothalamic gliosis in patients with type 2 diabetes mellitus: a proof-of-concept study.

AIMS: This study aimed to evaluate the effect of pioglitazone on brown adipose tissue function and hypothalamic gliosis in humans. Brown adipose tissue and the hypothalamus are regarded as important potential pharmacological targets to metabolic diseases, and defining the impact of current therapies on their structure and/or function could provide therapeutic advance in this field. METHODS: Six patients with type 2 diabetes were treated for 24 weeks with pioglitazone 30 mg/day as an add-on therapy. Brown adipose tissue glucose uptake and volume were determined using 18F-FDG PET/CT scans; hypothalamic gliosis was determined using MRI scans; blood was collected for hormone and biochemistry measurements. All tests were performed at inclusion and six months after pioglitazone introduction. RESULTS: Pioglitazone treatment led to a significant 3% body mass increase. There were neither changes in cold-induced brown adipose tissue glucose uptake and volume nor changes in hypothalamic gliosis. CONCLUSIONS: This is a proof-of-concept study that provides clinical evidence for a lack of action of a thiazolidinedione, pioglitazone, to promote homogeneous and measurable changes in brown adipose tissue volume and also in hypothalamic gliosis after 6 months of treatment.

[Hypothalamic dysfunction in obesity]. / Disfunção hipotalâmica na obesidade.

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.

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.

Partial reversibility of hypothalamic dysfunction and changes in brain activity after body mass reduction in obese subjects.

OBJECTIVE: Inflammation and dysfunction of the hypothalamus are common features of experimental obesity. However, it is unknown whether obesity and massive loss of body mass can modify the immunologic status or the functional activity of the human brain. Therefore, the aim of this study was to determine the effect of body mass reduction on brain functionality. RESEARCH DESIGN AND METHODS: In humans, changes in hypothalamic activity after a meal or glucose intake can be detected by functional magnetic resonance imaging (fMRI). Distinct fMRI analytic methods have been developed to explore changes in the brain's activity in several physiologic and pathologic conditions. We used two analytic methods of fMRI to explore the changes in the brain activity after body mass reduction. RESULTS: Obese patients present distinct functional activity patterns in selected brain regions compared with lean subjects. On massive loss of body mass, after bariatric surgery, increases in the cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and IL-6 are accompanied by changes in fMRI patterns, particularly in the hypothalamus. CONCLUSIONS: Massive reduction of body mass promotes a partial reversal of hypothalamic dysfunction and increases anti-inflammatory activity in the CSF.