Obesity: Will withaferin win the war?

A new study shows that withaferin A, a steroidal lactone isolated from Withania somnifera, can exert profound metabolic benefits in mice, including body-weight loss, reduced hepatic steatosis and improved glucose control

Physiological and epigenetic features of yoyo dieting and weight control.

Obesity and being overweight have become a worldwide epidemic affecting more than 1.9 billion adults and 340 million children. Efforts to curb this global health burden by developing effective long-term non-surgical weight loss interventions continue to fail due to weight regain after weight loss. Weight cycling, often referred to as Yoyo dieting, is driven by physiological counter-regulatory mechanisms that aim at preserving energy, i.e. decreased energy expenditure, increased energy intake, and impaired brain-periphery communication. Models based on genetically determined set points explained some of the weight control mechanisms, but exact molecular underpinnings remained elusive. Today, gene-environment interactions begin to emerge as likely drivers for the obesogenic memory effect associated with weight cycling. Here, epigenetic mechanisms, including histone modifications and DNA methylation, appear as likely factors that underpin long-lasting deleterious adaptations or an imprinted obesogenic memory to prevent weight loss maintenance. The first part summarizes our current knowledge on the physiology of weight cycling by discussing human and murine studies on the Yoyo-dieting phenomenon and physiological adaptations associated with weight loss and weight re-gain. The second part provides an overview on known associations between obesity and epigenetic modifications. We further interrogate the roles of epigenetic mechanisms in the CNS control of cognitive functions as well as reward and addictive behaviors, and subsequently discuss whether such mechanisms play a role in weight control. The final two parts describe major opportunities and challenges associated with studying epigenetic mechanisms in the CNS with its highly heterogenous cell populations, and provide a summary of recent technological advances that will help to delineate whether an obese memory is based upon epigenetic mechanisms

Nutropioids, hedonism in the gut?

The opioid system plays a pivotal role in how our brain regulates hedonic components of ingestive behavior. Duraffourd et al. (2012) add the gut to this opioid landscape, demonstrating direct activation of periportal mu-opioid receptors by food-derived opioid peptides (nutropioids), and a gut-brain feedback spiral that culminates in enhanced satiety

Profound weight loss induces reactive astrogliosis in the arcuate nucleus of obese mice.

Objective: Obesity has been linked to an inflammation like state in the hypothalamus, mainly characterized by reactive gliosis (RG) of astrocytes and microglia. Here, using two diet models or pharmacological treatment, we assessed the effects of mild and drastic weight loss on RG, in the context of high-fat diet (HFD) induced obesity.Methods: We subjected HFD-induced obese (DIO) male C57BU6J mice to a weight loss intervention with a switch to standard chow, calorie restriction (CR), or treatment with the Glp1 receptor agonist Exendin-4 (EX4). The severity of RG was estimated by an ordinal scoring system based on fluorescence intensities of glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1 positive (Iba1), cell numbers, and morphological characteristics.Results: In contrast to previous reports, DIO mice fed chronically with HFD showed no differences in microglial or astrocytic RG, compared to chow controls. Moreover, mild or profound weight loss had no impact on microglial RG. However, astrocyte RG was increased in CR and EX4 groups compared to chow fed animals and strongly correlated to body weight loss. Profound weight loss by either CR or EX4 was further linked to increased levels of circulating non-esterified free fatty acids.Conclusions: Overall, our data demonstrate that in a chronically obese state, astrocyte and microglial RG is indifferent from that observed in age-matched chow controls. Nonetheless, profound acute weight loss can induce astrocyte RG in the hypothalamic arcuate nucleus, possibly due to increased circulating NEFAs. This suggests that astrocytes may sense acute changes to both the dietary environment and body weight

Hypothalamische Entzündung und metabolisches Syndrom.

Overweight and obesity are two key factors in development of the metabolic syndrome. In recent years the major focus was directed towards elucidating how impairment of the central nervous system affects food intake and the development of obesity and insulin resistance. It has been shown in animal models and in humans that overconsumption of an energy-dense, high-fat diet leads to fundamental structural and functional changes of hypothalamic nuclei which govern eating behavior. Several recent scientific studies suggested that these nutritionally induced hypothalamic effects and changes, i.e. apoptosis of hypothalamic neurons and glial cells and subsequent local inflammatory processes, modulate eating behavior and metabolism in a defined way paving the way for development of obesity and eventually also the metabolic syndrome. This article summarizes findings from current related studies, introduces some of the underlying molecular mechanisms and shows how this knowledge might be used to develop novel treatment options for patients suffering from obesity and the metabolic syndrome

Measurement of monoamines in murine tissue.

Monoamines play a critical role as neurotransmitters and hormones in the functioning of brain and body of all mammals and are therefore often connected to diseases like Parkinson’s Disease or Diabetes. Up until now, catecholamines and related monoamines are routinely measured only in blood and plasma, as well as in the brain, for diagnostics and research in mouse models, respectively. But, as the monoamine pathways are complex and are present throughout the whole body, it would be important to have the means to analyze them in other body parts as well. Therefore, we, the group of Molecular EXposomics (MEX) at the Helmholtz Center Munich, focused on the development of a method for the measurement of these compounds in other tissues than brain. For this, the targets were different muscles (gastrocnemius, soleus, EDL), liver, pancreas, and brown and white adipose tissue. A simple clean up and extraction was developed for each of these tissues. The instrument for this method was a HPLC, fitted with a new generation solid core particle C-18 column and an amperometric electrochemical detector from Dionex. The sensitivity of this setup ranged from 0.625 pg/µl to 2.5 pg/µl. The analytes which could be differentiated, are the catecholamine dopamine, its metabolites 3,4‑dihydroxyphenylacetic acid, 3‑methoxytyramine, and homovanillic acid, the catecholamines norepinephrine, epinephrine, their metabolite 3‑methoxy‑4‑hydroxyphenylglycol, as well as the monoamine serotonin and its degradation product 5-hydroxyindoleacetic acid. These compounds could be found with different occurrence and concentrations in the analyzed tissues. However, for some of these tissues a few of the analytes were close to or below the limit of detection. To improve upon this, a new UHPLC instrument with a coulometric detector was procured. This instrument allows for greater sensitivity ranging from 0.25 pg/µl to 0.5 pg/µl. This system is now tested on other samples, e.g. brain perfusates, which have a very small sample volume and therefore need the greater sensitivity. Also completely new tissues like placenta, which could be useful in the diagnostics of early onset or predisposition of diseases, are currently tested

Comprehensive analysis of nine monoamines and metabolites in small amounts of peripheral murine (C57Bl/6J) tissues.

Monoamines, acting as hormones and neurotransmitters, play a critical role in multiple physiological processes ranging from cognitive function and mood to sympathetic nervous system activity, fight-or-flight response and glucose homeostasis. In addition to brain and blood, monoamines are abundant in several tissues, and dysfunction in their synthesis or signaling is associated with various pathological conditions. It was our goal to develop a method to detect these compounds in peripheral murine tissues. In this study, we employed a high-performance liquid chromatography method using electrochemical detection that allows not only detection of catecholamines but also a detailed analysis of nine monoamines and metabolites in murine tissues. Simple tissue extraction procedures were optimized for muscle (gastrocnemius, extensor digitorum longus and soleus), liver, pancreas and white adipose tissue in the range of weight 10-200mg. The system allowed a limit of detection between 0.625 and 2.5pg L-1 for monoamine analytes and their metabolites, including dopamine, 3,4-dihydroxyphenylacetic acid, 3-methoxytyramine, homovanillic acid, norepinephrine, epinephrine, 3-methoxy-4-hydroxyphenylglycol, serotonin and 5-hydroxyindoleacetic acid. Typical concentrations for different monoamines and their metabolization products in these tissues are presented for C57Bl/6J mice fed a high-fat diet