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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

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Physical Activity Attenuates Weight Gain Of FTO Gene?

Clearly genetic predisposition is one of the overwhelming risk factor for excess weight gain. This, however, does not mean that genetic risk is not modifiable. Thus, a paper by Carlos Celis-Morales and colleagues, published in OBESITY, suggests that physical activity may attenuate some of the weight gain attributable to the FTO gene, one of the more common obesity risk alleles. Their study includes data from 1,280 participants in the European Food4Me trial. Overall, the FTO (rs9939609) genotype was associated with a higher body weight of about 1 Kg per risk allele, 0.5 Kg/m2 higher BMI, and 1.1 cm greater waist circumference. While these “effects” were higher among inactive individuals (BMI by 1.06 kg/m2 per allele and waist circumference by 2.7 cm per allele), they were lower in individuals with moderate to high physical activity (BMI by 0.16 kg/me and Waist circumference by 0.5 cm). Thus, it appears that increased physical activity may attenuate (but not fully prevent) the effect of FTO genotype on BMI and WC. Exactly how clinically relevant these findings are and whether they would have any effect at all on public health messages or individual counselling, where increased physical activity is likely to be recommended irrespective of any “genetic markers” (or at least should be) is pretty doubtful. Currently, we have yet to await any practical consequences of genotyping individuals for obesity “risk” alleles. @DrSharma Edmonton, AB

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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

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Is Childhood Obesity Driven By Genetic Differences in Appetite?

Genetics plays a big part in the development of childhood (and, for that matter, adult) obesity – some folks are simply more genetically prone to weigh gain than others. Now a study by Silje Steinbeckk and colleagues from Norway, published in JAMA Pediatrics, suggests that while genetic factors are important, these may not act through an effect on appetite or eating behaviour. The longitudinal study was conducted in a representative birth cohort at the Trondheim Early Secure Study, enrolled at age 4 years during 2007 to 2008, with follow-ups at ages 6 and 8 years. Analyses included 652 children with genotype, adiposity, and appetite data. While there was clear effect of genetic risk (measured as a composite score of 32 genetic variants) on increase in body weight and fat mass), there was no clear relationship to appetite traits measured at age 6 years with the Children’s Eating Behavior Questionnaire. Thus, the authors conclude that while genetic risk for obesity is associated with accelerated childhood weight gain, appetite traits may not be the most promising target for preventing excessive weight gain. So if not through appetite, how do these genes increase the risk for weight gain. Obviously there are a number of possibilities ranging from subtle effects on energy metabolism, adipocyte differentiation or other factors that may not directly be related to eating behaviour. Another possibility may well be that the instrument used to assess appetite traits may simply not be sensitive and reliable enough to capture subtle changes in ingestive behaviour. Thus, while there is no doubt that genetic risk may well be a key determinant of childhood obesity, exactly how this effect is mediated remains unclear. @DrSharma Kelowna, AB

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Transcriptional Control of Energy Regulation

To students of human physiology, the commonly held view that obesity is simply a matter of energy in and energy out is nothing short of laughable. Indeed, there are perhaps no other biological functions of more importance for survival of an organism, than those that regulate energy uptake, storage and expenditure – functions, without any form of life would be impossible. Thus, the finely tuned complex and often highly redundant pathways that have evolved to optimize energy metabolism have evolved to readily switch from states of feeding to starvation with shifts in substrate use (both qualitative and quantitative) – functions that are controlled by hundreds (if not thousands) of genes. Getting these genes to work in concert, requires a complex system of gene regulation, by which individual genes are switched on an off (to allow or stop protein synthesis) in various tissues to just the right amount at just the right time – a process known as transcriptional control. Now, a comprehensive review by Adelheid Lempradl and colleagues, published in Nature Genetics, summarizes the multitude of interlinked processes that control transcription of genes involved in energy homeostasis. As the authors explain, “Transcriptional control is the sum of the cellular events that select and dose gene transcription. In simple terms, these events converge on the regulation of gene locus accessibility and polymerase activity (including recruitment, pausing, processivity and termination).” “Energy homeostasis requires multi-layered regulation via dynamic, often periodic, expression of metabolic pathways to properly anticipate and respond to shifts in energy state.” “Transcription factors act by binding to specific regulatory DNA sequences, thus controlling the transcriptional output of defined target gene sets. They cooperate with co-regulators, which either promote (co-activators) or inhibit (co-repressors) transcription. Together, they build feedback networks and control the stability and responsiveness of energy homeostasis. Metabolic cells use receptors and metabolic machinery to generate specific signalling responses to endocrine inputs (for example, insulin, glucagon or leptin receptors) or metabolic inputs (for example, the primary energy metabolism machinery itself).” The papers goes on to discuss at length the various regulator, co-regulators and the plethora of epigenetic modifiers that determine how these factors do their job of activating or deactivating relevant genes throughout the body. Why is any of this important? “Rapid progress is currently being made in research on chromatin-based regulation of gene expression. Particular unknowns include the mechanisms that establish long-term set points or priming of gene expression. Identifying the processes that… Read More »

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