In my talks, I have often joked about how to best keep weight off – just carry around a backpack that contains the lost pounds to fool the body into thinking the weight is still there. It turns out that what was intended as a joke, may in fact not be all too far from how the body actually regulates body weight. As readers of these posts are well aware, body weight is tightly controlled by a complex neuroendocrine feedback system that effectively defends the body against weight loss (and somewhat, albeit less efficiently, protects against excessive weight gain). Countless animal experiments (and human observations) show that following weight loss, more often than not, body weight is regained, generally precisely to the level of initial weight. With the discovery of leptin in the early 90s, an important afferent part of this feedback system became clear. Loss of fat mass leads to a substantial decrease in leptin levels, which in turn results in increased appetite and decreased metabolic rate, both favouring weight regain and thus, restoration of body weight to initial levels. Now, an international team of researchers led by John-Olov Jansson from the University of Gothenburg, Sweden, in a paper published in the Proceeding of the National Academy of Science (PNAS), provides compelling evidence for the existence of another afferent signal involved in body weight regulation – one derived from weight-bearing bones. Prompted by observations that prolonged sedentariness can promote weight gain, independent of physical activity, the researchers hypothesised that, “…there is a homeostat in the lower extremities regulating body weight with an impact on fat mass. Such a homeostat would (together with leptin) ensure sufficient whole body energy depots but still protect land-living animals from becoming too heavy. A prerequisite for such homeostatic regulation of body weight is that the integration center, which may be in the brain, receives afferent information from a body weight sensor. Thereafter, the integration center may adjust the body weight by acting on an effector.” In a first series of experiments, the researchers observed that implanting a weight corresponding to about 15% of body weight into rodents (rats and mice), resulted in a rapid “spontaneous” adjustment in body weight so that the combined weight of the animal plus the weight implant corresponded more-or-less to that of control animals. Within two weeks of implanting the weights, ∼80% of the increased loading was counteracted by reduced… Read More »
As readers will be well aware, n terms of health risks, fat is not fat is not fat is not fat. Rather, whether or not body fat affects health depends very much on the type of body fat and its location. While there have been ample attempts at trying to describe body fat distribution with simple anthropometric tools like measuring tapes and callipers, these rather crude and antiquated approaches have never established themselves in clinical practice simply because they are cumbersome, inaccurate, and fail to reliably capture the exact anatomical location of body fat. Furthermore, they provide no insights into ectopic fat deposition – i.e. the amount of fat in organs like liver or muscle, a key determinant of metabolic disease. Recent advances in imaging technology together with sophisticated image recognition now offers a much more compelling insight into fat phenotype. In this regard, readers may be interested in a live webinar that will be hosted by the Canadian Obesity Network at 12.00 pm Eastern Standard Time on Thu, Nov 23, 2017. The webinar provides an overview of a new technology developed by the Swedish company AMRA, that may have both important research and clinical applications. The talk features Olof Dahlqvist Leinhard, PhD, Chief Scientific Officer & Co-Founder at AMRA and Ian Neeland, MD, a general cardiologist with special expertise in obesity and cardiovascular disease, as well as noninvasive imaging at the UT Southwestern Medical Center in Dallas, US. Registration for this seminar is free but seats are limited. To join the live event register here. I have recently heard this talk and can only recommend it to anyone interested in obesity research or management. @DrSharma Edmonton, AB
If there is one thing we know for sure about obesity management, it is the sad fact, that no diet, exercise, medication, not even bariatric surgery, will permanently reset the body’s tendency to defend and regain its body weight to its set point – this generally being the highest weight that has been achieved and maintained for a notable length of time. Thus, any effective long-term treatment has to offset the complex neurobiology that will eventually doom every weight-loss attempt to “failure” (no, anecdotes don’t count!). Just how complex and overpowering this biological system that regulates body weight is, is described in a comprehensive review by the undisputed leaders in this field (Michael Schwartz, Randy Seeley, Eric Ravussin, Rudolph Leibel and colleagues) published in Endocrine Reviews. Indeed the paper is nothing less than a “Scientific Statement” from the venerable Endocrine Society, or, in other words, these folks know what they’re talking about when it comes to the science of energy balance. As the authors remind us, “In its third year of existence, the Endocrine Society elected Sir Harvey Cushing as President. In his presidential address, he advocated strongly in favor of adopting the scientific method and abandoning empiricism to better inform the diagnosis and treatment of endocrine disease. In doing so, Cushing helped to usher in the modern era of endocrinology and with it, the end of organo-therapy. (In an interesting historical footnote, Cushing’s Energy Homeostasis and the Physiological Control of Body-Fat Stores presidential address was given in , the same year that insulin was discovered.)” Over 30 pages, backed by almost 350 scientific citations, the authors outline in excruciating detail just how complex the biological system that regulates, defends, and restores body weight actually is. Moreover, this system is not static but rather, is strongly influenced and modulated by environmental and societal factors. Indeed, after reading this article, it seems that the very notion, that average Jane or Joe could somehow learn to permanently overcome this intricately fine-tuned system (or the societal drivers) with will power alone is almost laughable (hats off to the very few brave and determined individuals, who can actually do this – you have climbed to the top of Mount Everest and decided to camp out there for the foreseeable future – I wish you all the best!). Thus, the authors are confident that, “The identification of neuromolecular mechanisms that integrate short-term and long-term control… Read More »
Regular readers may recall previous posts on the novel anti-obesity compound belanorib, a MetAP2 inhibitor that showed remarkable weight loss efficacy both in patients with Prader-Willi Syndrome as well as hypothalamic obesity. Unfortunately, as noted before, several cases of venous thromoboembolisms led to a halt of ongoing trials during which the company (Zafgen) sought to better understand the possible mechanism for this serious adverse effect and explore the possibility of implementing a risk mitigation strategy. As announced by the company in a press release earlier this week, “Following its discussions with the FDA and review of other considerations, Zafgen has determined that the obstacles, costs and development timelines to obtain marketing approval for beloranib are too great to justify additional investment in the program, particularly given the promising emerging profile of ZGN-1061. The Company is therefore suspending further development of beloranib in order to focus its resources on ZGN-1061.” The press release also describes the new compound ZGN-1061 as a, “…fumagillin-class, injectable small molecule second generation MetAP2 inhibitor that was discovered by Zafgen’s researchers and has been shown to have an improved profile relative to previous inhibitors in the class. Like other MetAP2 inhibitors that have shown promise in the treatment of metabolic diseases including severe and complicated obesity, ZGN-1061 modulates the activity of key cellular processes that control the body’s ability to make and store fat, and utilize fat and glucose as an energy source. ZGN-1061 is also anticipated to help reduce hunger and restore balance to fat metabolism, enabling calories to once again be used as a productive energy source, leading to weight loss and improved metabolic control. ZGN-1061 has an emerging safety profile and dosage form that are believed to be appropriate for the treatment of prevalent forms of severe and complicated obesity, and is currently in Phase 1 clinical development. Zafgen holds exclusive worldwide rights for the development and commercialization of ZGN-1061.” According to the press release, “The compound has similar efficacy, potency, and range of activity in animal models of obesity as beloranib, but displays highly differentiated properties and a reduced potential to impact thrombosis, supporting the value of the compound as a more highly optimized MetAP2 inhibitor.” Screening of patients for a Phase 1 clinical trial evaluating ZGN-1061 for safety, tolerability, and weight loss efficacy over four weeks of treatment is currently underway. @DrSharma Edmonton, AB Disclaimer: I have served as a consultant to Zafgen.
There is little doubt that increased consumption of fructose-sweetened beverages can be a substantial source of extra calories, thereby potentially promoting weight gain. That said, fructose has also been implicated in non-caloric metabolic effects including promoting insulin resistance and systemic inflammation. Now a study by Jessica Kuzma and colleagues from the Fred Hutchinson Cancer Research Center, Seattle, WA, published in the American Journal of Clinical Nutrition, specifically addresses the hypothesis that fructose-sweetened beverages can promote systemic inflammation. For their study, they randomised 24 otherwise healthy participants to three 8 day periods during which participants consumed 4 daily servings of fructose-, glucose-, or HFCS-sweetened beverages accounting for 25% of estimated calorie requirements while consuming a standardized diet ad libitum. During the study subjects consumed 116% of their estimated calorie requirement while drinking the beverages with no difference in total energy intake or body weight. Neither fasting plasma concentrations of C-reactive protein or IL-6 changed during the study. Furthermore, there were no consistent changes in measures of adipose tissue inflammation or in intestinal permeability. Overall, the researchers conclude that consuming an excessive amount of fructose, HFCS, and glucose derived from SSBs consumed, at least in the short term (8 days), does not appear to promote systemic inflammation in otherwise healthy adults. Obviously, this study does not address the issue of wether or not overconsumption of sugar-sweetened beverages can promote obesity or whether cutting out such beverages has any other advantages short of lowering caloric consumption. @DrSharma Edmonton, AB