For all my Canadian readers (and any international readers planning to attend), here just a quick reminder that the deadline for early bird discount registration for the upcoming 4th Canadian Obesity Summit in Toronto, April 28 – May 2, ends March 3rd.
To anyone who has been at a previous Canadian Summit, attending is certainly a “no-brainer” – for anyone, who hasn’t been, check out these workshops that are only part of the 5-day scientific program – there are also countless plenary sessions and poster presentations – check out the full program here.
To register – click here.
During my current visit to speak at the Icelandic Medical Association Annual Conference and meet with policy makers, my hosts are doing a wonderful job of introducing me to their “Nordic” fare consisting largely of fish, rye bread and other local produce.
Reason enough to post on this recent article by Marjukka Kolehmainen and her team of Scandinavian colleagues, published in the American Journal of Clinical Nutrition, which examines the effects of a Nordic diet on the expression of inflammatory markers in adipose tissue of individuals with the metabolic syndrome.
Participants in this 18-24 week study were randomised to either a Nordic or control diet in the SYSDIET study, whereby participants for this “substudy” were selected from centres in Kuopio, Lund and Oulo. Importantly, subjects chosen for this analysis were relatively weight stable, having lost or gained less than 5% of their body weight during the course of the study.
In accordance with recommendations for a healthy Nordic diet, subjects in the intervention group were counselled to increase their consumption of whole-grain products, berries, fruits and vegetables, rapeseed oil, have three fish meals per week, and chose low-fat dairy products, while avoiding sugar-sweetened products. In contrast, the control group was advised to consume low-fiber cereal products and dairy fat–based spreads while limiting their fish intake to that generally consumed by the average Nordic population.
Gene expression studies were performed in biopsies from subcutaneous fat tissue and showed differential expression of about 130 genes between the two dietary groups – most of which were related to pathways involved in immune and inflammatory response, including genes involved in leukocyte trafficking and macrophage recruitment (e.g., interferon regulatory factor 1, CD97), adaptive immune response (interleukin32, interleukin 6 receptor), and reactive oxygen species (neutrophil cytosolic factor 1).
Together, the analyses showed a significant reduction in many of these markers consistent with an “anti-inflammatory” effect of the Nordic diet.
As the authors point out, these beneficial effects were seen with very little or no weight loss, suggesting that they are indeed attributable to the changes in dietary intake.
These findings may well have implications for us here in Canada, where eating a “Nordic” diet with local ingredients, may well be a far better alternative than trying to emulate a “Mediterranean” diet, the green house impact of which would be anything but healthy.
This happened last week, when Stephanie Simonds and an international group of researchers, in a paper published in Cell, present a rather elegant and sophisticated range of studies clearly demonstrating that the adipocyte-derived hormone leptin is a key mediator of hypertension in diet-induced (and probably other types of) obesity.
The reason I thought that this question had already long been put to rest was due to a series of rather convincing animal and human studies published in the early 2000s (some of which I was directly involved in) that nicely demonstrated a) that obesity in hypertension is largely mediated by an increase in (renal) sympathetic activity; b) that leptin stimulates sympathetic activity and sodium retention; c) in dogs and humans leptin concentrations are closely correlated with sympathetic nerve activity and blood pressure. We’ve also known that obese mice lacking leptin or its receptor do not develop hypertension despite considerable weight gain.
If anyone should have any remaining questions, these are now answered in the paper by Simonds and colleagues which uses an array of experiments involving animals deficient in leptin or leptin receptors, humans with loss-of-function mutations in leptin and the LepR and show that leptin’s effects on blood pressure are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), an effect that is prevented or reversed by blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH.
All of this is interesting and highlights the fact that adipose tissue is far more than a simple storage organ for fat but rather a tissue that plays an active role in the regulation of a wide range of bodily functions.
Leptin alone, just one of the many hormones secreted by fat cells (often collectively referred to as adipokines), has been shown to play an important role in appetite and energy regulation, immune function and bone development.
As for bringing us a step closer to obesity treatments, the study suggests that it may not be easily possible to harness leptin as a treatment for weight loss, as one expected side effect would be an increase in blood pressure and heart rate – effects that have limited the clinical tolerability of other “sympathomimetic” drugs.
Hypothalamic obesity, is a rare but serious condition that occurs in about 50% of individuals who have suffered injury to their hypothalamus (e.g. because of a craniopharyngoma or trauma).
Severe weight gain in these patients may not be all that surprising given that the hypothalamus plays a key role in the regulation of hunger, satiety and other aspects of energy balance.
Now, Zafgen, a US biopharmaceutical company, announces surprising early results of treating such patients with beloranib, an inhibitor of methionine aminopeptidase 2 (MetAP2), an enzyme that modulates the activity of key cellular processes that control metabolism.
According to Zafgen, their small proof-of-principle trial (ZAF-221), conducted in 14 obese patients (nine women and five men) who were confirmed by magnetic resonance imaging (MRI) to have had hypothalamic injury, the results look most promising.
Here is the description of their findings taken from their press release:
“ZAF-221 was a randomized, double-blind, placebo controlled study of twice-weekly subcutaneous injections of 1.8 mg beloranib or placebo in patients with HIAO to evaluate weight reduction and safety over four weeks, followed by an optional four week open-label extension. Beloranib treatment resulted in mean weight loss of 3.4 kg and 6.2 kg in patients with HIAO after four and eight weeks of treatment with beloranib, respectively, in contrast to 0.3 kg mean weight loss in patients treated with placebo for four weeks (p = 0.01). Improvements in cardiovascular disease risk factors of lipids and inflammation (measured by C-reactive protein) were also observed. Beloranib 1.8 mg was well tolerated in this population, with no serious or severe adverse events reported. Safety measures such as laboratory, electrocardiogram, and vital sign measurements revealed no signals of concern, and all subjects randomized to beloranib completed the trial.”
What I find most surprising about these findings, is that this drug appears to work in people where key centres for appetite regulation are no longer intact. This points to the existence of a non-hypothalamic mode of action for this drug – an action that is powerful enough to work independently of the centres in the brain known to play a key role in energy regulation.
Needless to say, this finding may well also hold promise for other forms of obesity, reason enough to closely watch the further development of this compound.
Disclaimer: I have served as a paid consultant to Zafgen.
The answer may well be “yes”, at least if you happen to be a mouse.
In a rather exciting study by Iliana López-Soldado and colleagues from the Institute for Research in Biomedicine, Barcelona, published in DIABETES, the researchers show that increased liver glycogen content may affect appetite (measured as food intake) and otherwise have beneficial effects on metabolism.
In their experiments, the researchers used genetically modified mice, which overexpress an enzyme (PTG) resulting in increased liver glycogen.
Not only did these animals reduce their food intake when fed a high fat diet, they also did not develop the typical glucose intolerance, elevated insulin levels and fatty liver seen in normal mice on this diet.
Apart from losing weight (associated with lower leptin levels), these animals also had lower expression of neuropeptide Y (NPY) and higher expression of propiomelanocortin (POMC) in the hypothalamus.
Thus, the authors summarize their findings as follows:
:…liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of a HFD and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.”
As a number of compounds exist that may do exactly that, these studies may point to a novel pathway for the pharmacological treatment of obesity – but let’s keep in mind that the road from finding in mice to effective treatments in humans is a long and thorny road.
López-Soldado I, Zafra D, Duran J, Adrover A, Calbó J, & Guinovart JJ (2014). Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model. Diabetes PMID: 25277398