How the FTO Gene Contributes to Obesity
While I took a month off from blogging, an international group of researchers published what may well become a landmark paper on the genetics of obesity in the New England Journal of Medicine. As regular readers may be well aware, a number of previous genetic studies have pointed to the importance of the FTO gene for human obesity – however, what exactly this gene does to effect body weight was largely unclear. The rs1421085 single-nucleotide variant of this gene has both a high frequency and a strong effect size, which suggests positive selection or bottlenecks (e.g., 44% frequency in European populations vs. 5% in African populations). In the present paper, that included examination of epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns in mice and humans, the researchers showed that the FTO allele associated with obesity represses mitochondrial energy production in adipocyte precursor cells in a tissue-autonomous manner. To be precise, the rs1421085 variant of this gene apparently disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. These molecules play key roles in thermogenic dissipation both through UCP-1 and UCP-1-independent pathways. This change leads to a persistent and cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5. It is also associated with an increase in lipid storage and adipocyte cell size. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from human subjects with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Finally, repair of the ARID5B motif in primary cultured adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. These deep insights into the function of what is apparently a key pathway in human susceptibility (or resistance) to obesity, offers a number of potential targets for pharmacological interventions for obesity – something that we desperately need for patients struggling with this issue. However, as an accompanying editorial is quick to point out, “As yet, there… Read More »
Cognitive And Autonomic Determinants of Energy Balance
While I’m here at the 10th Canadian Obesity Network Summer School (Boot Camp), in the Canadian Rockies, it is perhaps of interest to note that one of the founding faculty of this school, Denis Richard from Laval University, has just published a paper in Nature Reviews Endocrinology, which nicely reviews the complex neurobiology of energy balance. The paper focuses largely on the “energy out” part of energy homeostasis, which is partly determined by the themogenesis of brown adipose tissue and mediated by the sympathetic nervous system. Thus, several areas of the brain work together in complex neuronal networks involving a host of neuronal systems including the opioid, endocannabinoid and melanocortin systems, that not only control appetite and eating behaviour but also thermogenesis. These neuronal systems, in turn receive inputs from a wide range of peripheral organs including the gut, liver and adipose tissue via hormonal and neuronal pathways that signal energy stores and nutritional status. The paper also discusses how some of these findings may be relevant to the development of novel treatments for obesity. For researchers and students: the paper includes a number of excellent graphics that nicely illustrate these systems. @DrSharma Kananaskis, AB
Dose-Response Relationship Between Obesity And Breast Cancer
With all the concern about the impact of obesity on metabolic and cardiovascular health, it is often forgotten that after smoking, obesity is the single most important risk factor for many common cancers, including of course breast cancer. The importance of this relationship is again documented by Marian Neuhouser and colleagues in a paper published in JAMA Oncology. The study examines the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up (about 13 years) in the Women’s Health Initiative (WHI) clinical trials, involving over 67,000 postmenopausal women ages 50 to 79 years at 40 US clinical centers.. Overall, 3388 invasive breast cancers were observed over the follow-up period with women who were overweight or obese having increased risk that was related to their degree of excess weight. Compared to normal weight women, individuals with Class II and III obesity had a 60% greater risk for invasive breast cancer with an almost 2-fold greater risk for estrogen receptor–positive and progesterone receptor–positive breast cancers. Class II and III obesity was also associated with a 2-fold greater risk for larger tumor size, positive lymph nodes and deaths. Furthermore, risk was increased in women with a baseline BMI of less than 25.0 who gained more than 5% of body weight over the follow-up period. Given this importance of obesity for breast cancer, one can only wonder just how much of the Cancer research funding raised by the Pink Ribbon campaign and other Cancer charities, finds its way into research on obesity treatment and prevention – can’t say I know of any cancer funding that has knocked on the doors of my fellow obesity researchers. @DrSharma Edmonton, AB
3,500 Cal Per Pound Is More Like 4,500 Cal
Note: see comment #1 One of the most persistent notions about equating caloric deficit to weight loss is the 3500 Cal “rule”. I have previously posted about why this is nonsense and not exactly helpful when it comes to thinking about clinical weight loss or weight (you’re dealing with physiology NOT physics!). Now, Nicholas Gwerder, a student from the University of Sacramento, in his Master Thesis, has apparently reviewed the literature on this and concludes that if anything, one pound of weight loss comes closer to 4,500 calories. Gwerder reaches this conclusion by analysing data from 28 studies in which he compares the theoretical weight loss to the actual weight (and fat) lost in these studies. Although, I do not have access to Gwerder’s Master Thesis, here is what he says in the summary: “The energy equivalent of body weight loss varied considerably, dependent upon the constituent portions of fat, water, protein, carbohydrate and mineral lost. Adipose tissue also varied with type and was dependent upon the composition of lipid, water, and protein. The most valid theoretical equivalent for a pound of fat was calculated at 4,423.90 kilocalories based on in vivo extraction of human intracellular lipid samples.” Thus, as Gwerder points out, the 3,500 per pound notion tossed around (including by a number of guidelines and associations) “…severely underestimates the caloric values needed to achieve desired fat mass loss. This use of the proper caloric value for fat mass loss has the potential to improve exercise and nutrient recommendations for achieving healthy body fat values.” Thus, if this number holds true, a daily 500 Cal deficit maintained over 10 weeks will not give you a 10 pound weight loss, but rather only about 7.5 lbs. All the same, in practice over time this never really works out, not just because of the individual variability (Gwerder notes about 20% variation in this relationship) but because as you reduce your caloric intake, your individual metabolic requirements will very quickly shift to living off fewer calories, which means that pretty soon into your diet, the initial 500 Cal deficit is no longer a deficit (thank your physiology). This is the feared weight-loss plateau – the frustration of every dieter. So, whether 3,500 or 4,500 Cal per pound, the relationship between calorie restriction and weight loss is not linear and thus extrapolating the amount of expected weight loss based on this deficit seldom… Read More »
Post-Weight Loss Fat Gain in US Rangers
And finally, to conclude this week’s discussion of evidence to support the notion that weight cycling predicts weight (fat) gain especially in normal weight individuals, I turn back to the paper by Dulloo and colleagues published in Obesity Reviews, which quotes these interesting findings in US Rangers: “…U.S. Army Ranger School where about 12% of weight loss was observed following 8–9 weeks of training in a multi-stressor environment that includes energy deficit. Nindl et al. reported that at week 5 in the post-training recovery phase, body weight had overshot by 5 kg, reflected primarily in large gains in fat mass, and that all the 10 subjects in that study had higher fat mass than before weight lost. Similarly, in another 8 weeks of U.S. Army Ranger training course that consisted of four repeated cycles of restricted energy intake and refeeding, Friedl et al. showed that more weight was regained than was lost after 5 weeks of recovery following training cessation, with substantial fat overshooting (∼4 kg on average) representing an absolute increase of 40% in body fat compared with pre-training levels. From the data obtained in a parallel group of subjects, they showed that hyperphagia peaked at ∼4 weeks post-training, thereby suggesting that hyperphagia was likely persisting over the last week of refeeding, during which body fat had already exceeded baseline levels.” Obviously, association (even in a prospective cohort) does not prove causality or, for that matter, provide insights into the physiological mechanisms underlying this observation. All we can conclude, is that these observations in US Rangers (and the other studies cited in Dulloo’s article) are consistent with the notion that weight loss in normal weight individuals can be followed by significant weight gain, often overshooting initial weight. Incidentally, these findings are also consistent with observational studies in women recovering from anorexia nervosa, famine, cancer survivors and other situations resulting in significant weight loss in normal weight individuals. Certainly enough evidence to consider a work of caution against “recreational” weight loss, especially in individuals of normal weight. @DrSharma Edmonton, AB Dulloo AG, Jacquet J, Montani JP, & Schutz Y (2015). How dieting makes the lean fatter: from a perspective of body composition autoregulation through adipostats and proteinstats awaiting discovery. Obesity reviews : an official journal of the International Association for the Study of Obesity, 16 Suppl 1, 25-35 PMID: 25614201
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