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.
Yesterday’s guest post on the issue of food addiction (as expected) garnered a lively response from readers who come down on either side of the discussion – those, who vehemently oppose the idea and those, who report success.
Fact is, that we can discuss the pros and cons of this till the cows come home, because the simple truth is that the whole notion lacks what my evidence-based colleagues would consider “strong evidence”.
Indeed, I did try to find at least one high-quality randomized controlled study on using an addictions approach to obesity vs. “usual” care (or for that matter anything else) and must admit that I came up short. The best evidence I could find comes from a few case series – no controls, one observer, nothing that would compel anyone to believe that this approach has more than anecdotal merit.
Yet, the biology (and perhaps even the psychology) of the idea is appealing. Self-proclaimed “food addicts” that I have spoken to readily identify with the addiction model and describe their relationship to “trigger foods” as an uncontrollable factor in their lives that calls for complete abstinence. Animal studies confirm that foods do indeed stimulate the same parts of the brain that are sensitive to other hedonic pleasures and substances.
So why the lack of good data? After all, the idea is hardly new – intervention programs for “food addicts” using the 12 steps or other approaches have been around for decades.
Can it be simply the lack of academic interest in this issue? I find that hard to imagine – but nothing would surprise me.
Is it perhaps because addiction researchers do not take obesity seriously and obesity researchers don’t like the addiction model?
I certainly don’t buy the argument that there is no commercial interest in such an approach – if there were strong and irrefutable evidence, I’m sure someone would figure out how to monetize it.
So again, I wonder, why the lack of good data?
Honestly, I don’t know.
I’m open to any views on this (especially if substantiated by actual evidence).
Thus, a study by Miram Salama and colleagues from Laval University, QC, published in Physiology and Behavior, shows that mental work may very much influence food preferences and satiety.
Using a cross-over design, 35 healthy young adults were randomly assigned the one of the two following conditions: mental work (reading a document and writing a summary of 350 words with the use of a computer) or control (rest in seated position).
After 45 mins of each condition, participant were offered a standardized ad libitum buffet-type meal. Appetite sensations (desire to eat, feeling of hunger, fullness level and estimated amount of food that can be consumed) were measured using a visual analogue scale (VAS).
While women not only had a higher caloric intake after the mental work (by about 100 extra Cal), men reduced their caloric intake (by about 200Cal).
While women selectively increased their preference for carbs, men reduced their intakes of dessert.
In both men and women, participants with the highest waist circumference also had the lowest satiety efficiency in response to mental work.
These results suggest that mental work can change energy intake and preferences in both men and women, albeit in different directions.
Why this would be is anyone’s guess – it is also not clear exactly how this mechanism works. One speculation would be that there are differences in how men and women respond to mental stress – but that is certainly work for a future study.
As regular readers of these posts are well aware, the Holy Grail of obesity is how to lower the body weight setpoint , which tends to reset to progressively higher weights with weight gain and then acts to “defend” against weight loss, virtually guaranteeing weight regain in the vast majority of people who try to lose weight.
Now, a study by Yonwook Kim and Sheng Bi published in the American Journal of Physiology, shows that knocking down neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) can reverse the weight gain induced by a high-fat diet in rats.
Following the induction of significant weight gain by feeding rats a high-fat diet (HFD), which not only increased body weight but also induces insulin resistance, the obese rats received bilateral DMH injections of an adenovirus vector that specifically knocked down NPY in this region of the brain.
Not only did the NPY knockdown rats exhibit normal food intake and a reduced body weight, their glucose tolerance and insulin sensitivity also reverted to that seen in lean control rats, an effect that was maintained even over weeks of follow up.
While these studies do not exactly prove the importance of NPY in the establishment or maintenance of the body weight “set point”, they do suggest that blocking NPY in the DMH (e.g. through an NPY inhibitor) may provide a potential target for the treatment of obesity and diabetes.
Now Rhythm Pharmaceuticals released its first data on the use of their novel MC4-R agonist setmelanotide in patients with obesity and proven MC4-R defects.
According to their press release,
“In this pilot study, obese (BMI >/= 30kg/m2) patients with a heterozygous MC4R loss-of-function mutation were enrolled in a double-blind, placebo-controlled, randomized, parallel-group study for 4 weeks. Eight patients (six active, two placebo) received placebo or RM-493 at 0.01 mg/kg/day (~ 1 mg/day) by continuous subcutaneous infusion. Key endpoints were safety, weight loss, waist circumference, and caloric intake. Setmelanotide was well tolerated over 4 weeks, with no serious adverse events or discontinuations. The most common side effects were headache and skin tanning, with the latter believed to be due to off-target activity at the related melanocortin-1 receptor. Setmelanotide demonstrated strong trends for placebo-subtracted weight loss (2.62 kg; p=0.088); WC (5.1 cm; p=0.188) and daily caloric intake (351 kCal/day; p=not significant), without clinically important effects on heart rate or blood pressure.”
Overall, the company has taken (the perhaps wise) option of focussing their development program on genetic forms of obesity.
Currently they have an ongoing Phase 2 setmelanotide trial for the treatment of Prader-Willi syndrome and a second Phase 2 trial for the treatment of pro-opiomelanocortin (POMC) deficiency obesity, a very rare, life-threatening genetic disorder of the MC4 pathway associated with unrelenting appetite and obesity.
Clearly, this will be a space to watch.