OGT: A Brain Nutrient Sensor That Controls Satiety?
Shortly after a meal, there is a spike in the cerebrospinal fluid concentration of nutrients with direct access to various nutrient-sensitive sites in the brain. Now a paper by Olof Lagerlöf and colleagues, published in SCIENCE, shows that in mice, the glycosylation enzyme O-GlcNAc transferase (OGT), present in a wide range of neurons involved in energy regulation and feeding behaviours, may play an important role in the satiety response. Genetic and molecular manipulation of this enzyme in adult mice resulted in marked effects on feeding and weight gain. Reducing the activity of the enzyme resulted in animals eating much larger meals (but not more often) with substantial gain in fat (but not lean) mass. In contrast, increasing the activity of this enzyme resulted in reduced food intake during eating episodes. Not only does it make sense that a molecule known to play a role as a nutrient-sensor would play a role in the central regulation of food intake, but the authors are optimistic that this enzyme may be a target for finding new anti-obesity medications. @DrSharma Edmonton, AB
Reduced Brain Impact of Eating in Obesity
Countless studies now show that there are important metabolic differences between people living with obesity and those living with normal weight. Of particular interest are studies showing difference in hormonal and neuronal response to eating. Now, a study by Nancy Puzziferri and colleagues from the University of Texas, published in OBESITY, show that the brain response to eating may differ substantially between people with normal weight and those living with obesity. The study was conducted in 15 women with severe obesity and 15 age-matched lean women (18-65 years old). When fasting, brain perfusion measured by arterial spin labeling was similar between obese and normal-weight volunteers and both groups showed significantly increased activity in the neo- and limbic cortices and midbrain activity in functional magnetic resonance imaging (fMRI). However, after a standard meal, the lean group showed significantly decreased activation in these areas, whereas the group with severe obesity showed no such decreases. In line with these findings, after eating, subjective appeal ratings of food decreased in lean but not in the obese women. As the researchers note, these findings are in line with previous brain imaging studies. “…after eating, participants with severe obesity maintain activation in the midbrain, one of the most potent reward centers. Thus, once satiated after eating, participants with severe obesity continue to perceive food as appealing and their brains continue to be activated by visual food cues as though they were hungry.” These finding would explain why individuals with obesity are perhaps at a far greater risk to continue eating (especially highly-palatable foods such as dessert) even when satiated. What these type of studies do not tell us whether these differences are primary (i.e. could have led to the weight gain in the first place) or secondary (i.e. the consequence of weight gain). Be that as it may, the findings do show that there are significant differences in how the brain responds to eating between people with obesity and those with normal weight. Clearly, the next step would be to see if this lack of response can be restored through weight loss (e.g. bariatric surgery) or through anti-obesity medication. At least the findings perhaps explain why simply telling people with an activated limbic system to “push away from the table” may not be all that effective. @DrSharma Edmonton, AB
Brain Renin-Angiotensin System And Body Weight
At one time in my research career, I was enamoured by the potential role of the renin-angiotensin system in the biology of adipose tissue – in fact, my lab was one of the first to characterize this system in human tissue. Since then, my interests have moved on to a other things but I still keep an eye open for research on this system as it relates to body weight. Thus, the recent work by Martina Winkler and colleagues from the University of Lübeck and the Max-Delbrück-Centre for Molecular Medicine in Berlin (where I used to work), published in the British Journal of Pharmacology caught my attention. The researchers studied rats with a brain-specific angiotensinogen deficiency compared to controls using various dietary regimens. Compared to SD rats, the brain-angioteninogen-deficient rats had lower weights during chow feeding, did not become obese during a high-caloric diet, had normal baseline leptin plasma concentrations independent of the feeding regimen, showed a reduced energy intake, had a higher, strain-dependent energy expenditure which is additionally enhanced during high-caloric feeding, had enhanced mRNA levels of pro-opiomelanocortin, and showed improved glucose control. While the Angiotensin type 1 receptor blocker telmisartan reduced weight gain and energy intake in control rats, it had less effect in the brain-angiotensin-deficient rats Thus, the researchers conclude that the brain renin-angiotensin system may play an important role in body weight regulation, feeding behavior, and metabolic disorders – at least in rats. How relevant these findings are for humans remains doubtful. For one, the widespread clinical use of inhibitors of the renin-angiotensin-system (ACE inhibitors, AT1 receptor blockers) are not generally associated with clinically significant weight loss. However, this may be because most of these agents do not reach high enough concentrations in human brain tissue. But it may also well be that this system is less important for body weigh regulation in humans than in rodents. @DrSharma Edmonton, AB
Join CON For Its First Public Webinar
One of the coming features of the Canadian Obesity Network’s patient engagement strategy is a new series of public webinars on topics relevant to obesity by Canadian experts. I will have the honour of giving the inaugural talk in this series on Tuesday, Feb 23, 2016, 12.00 pm (Eastern) on the topic of “why obesity is a chronic disease”. The webinar is free but seats are limited, so registration for this event is recommended. You can also join the discussion on Facebook. In case you miss it, the talk will be posted on the CON website after the event. Join me in looking forward to this and forthcoming webinars in this series. @DrSharma Edmonton, AB
Cold Exposure Promotes Gut Microbes That Stimulate Brown Fat
It seems that there is no end to how intimately gut microbes are linked to metabolic function. Thus, a study by Claire Chevalier and colleagues from Geneva, Switzerland, published in CELL, not only shows that cold exposure (of mice) changes their gut microbes but also that, when transplanted into sterile mice, these “cold” microbes stimulate the formation of thermogenic brown fat. All of this makes evolutionary sense, as the increase in heat-generating (and calorie-burning) brown fat with cold exposure would protect the organism against cold exposure – however, that gut bacteria would be involved in this process is indeed rather surprising. Unfortunately, at least for those thinking that “cold bacteria” may be the panacea for stimulating brown fat and thus weight loss are likely to be disappointed. The researchers also show that with prolonged exposure to cold, these “cold bacteria” induce changes to the structure and function of the gut that enable more glucose to be absorbed. While in the short-term, this extra fuel can be used by the brown fat to generate heat, in the long-term, some of these extra calories probably go towards building more white fat and thus weight gain. Again, this makes evolutionary sense. After all, it is ecologically a far better strategy to insulate the house than to waste extra calories heating it. This is why, the naive notion that simply lowering ambient temperature as a means to generate more brown fat and thus, burn more calories, may not be all that effective. Indeed, these experiments suggest rather that chronic cold exposure would ultimately stimulate extra insulation, i.e. more subcutaneous fat and weight gain. Funnily enough, these findings turn the hypothesis that reducing room temperature would promote weight loss into exactly the opposite. Perhaps it is the excessive use of air-conditioning to generate freezing indoor temperatures (as any European visitor to the US will readily attest to), is part of the problem. Fascinating stuff for sure. @DrSharma Gurgaon, Haryana
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