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.
This, according to a study by Ruth Brown and colleagues from Toronto’s York University, published in Medicine and Science in Sports and Exercise.
The study included 58 adult men and women of either normal weight (NW) or overweight (OW), who reported either attempting (WL) or not attempting weight loss (noWL)
Following 25 mins of exercise on a treadmill at either a moderate (60% HRmax) or a vigorous intensity (75% HRmax), participants were asked to estimated the number of calories they expended through exercise and create a meal that they believed to be calorically equivalent to the amount of calories they had just burnt.
Both the moderate and intense exercise groups were on average spectacularly wrong in their estimates.
In contrast, the active weight loss (WL) groups appeared to do far better at estimating energy consumption than the non-WL groups.
As an example, following vigorous exercise, the OW-noWL overestimated energy expenditure by 72%, and overestimated the calories in their food by 37%.
Although the WL groups did better, all groups showed a wide range of over and underestimation (-280 kcal to +702 kcal).
These findings show that while most people tend to over or underestimate caloric expenditure with exercise, overweight adults who are not attempting weight loss may be even more off the mark than others.
The most obvious solution would be to use some kind of monitor that does a better job of predicting calories consumed that just guessing.
That is of course, if overcompensating is not your goal (as in people who actually gain weight when they begin exercising).
For those interested in staying in energy balance, perhaps simply stepping on the scale regularly during the week should be enough.
For those interested in losing weight, they may need to be reminded that exercise (alone) is actually a pretty inefficient way to lose weight, so the calories burnt during exercise probably don’t matter all that much for weight management (despite all other benefits of exercise – its the calories you eat or drink that count).
Now Suzanne Higgs and Jason Thomas from the University of Birmingham, UK, in a paper published in Current Opinion in Behavioral Science review the role of social norms in eating behaviours and discuss how these norms could potentially be targeted to improve eating behaviours.
“We eat differently when we are with other people compared with when we eat alone. Our dietary choices also tend to converge with those of our close social connections. One reason for this is that conforming to the behaviour of others is adaptive and we find it rewarding. Norms of appropriate eating are set by the behaviour of other people, but also shared cultural expectations and environmental cues. We are more likely to follow an eating norm if it is perceived to be relevant based on social comparison. Relevant norms are set by similar others and those with whom we identify… Norm matching involves processes such as synchronisation of eating actions, consumption monitoring and altered food preferences.”
“Social norms may have had a role to play in recent rises in obesity by reinforcing new behaviour patterns associated with overeating and weight gain. For example, increases in average portion size may have created new consumption norms that are diffused through social networks. It might also be that the social context of eating has changed recently in ways that favour overconsumption. For example, more people eating away from home in fast food restaurants with others might be associated with social facilitation of eating.”
If, how and to what extent, eating culture can be changed at a population level through public health and policy interventions will certainly remain the subject of further study.
Now a study by Robert Eckel and colleagues, published in Current Biology, illustrates how sleep deprivation and timing of meals can markedly alter insulin sensitivity.
Studies were conducted in 16 healthy young adults (8w) with normal BMI. Following a week of 9-hr-per-night sleep schedules, subjects were studied in a crossover counterbalanced design with 9-hr-per-night adequate sleep (9-hr) and 5-hr-per-night short sleep duration (5-hr) conditions lasting 5 days each, to simulate a 5-day work week. Sleep was restricted by delaying bedtime and advancing wake time by 2 hr each.
Energy balanced diets continued during baseline, whereas food intake was ad libitum during scheduled wakefulness of 5- and 9-hr conditions.
Overall, the simulated 5-day work week of 5-hr-per-night sleep together with an ad libitum diet resulted in a 20% decrease in oral and intravenous insulin sensitivity, which was compensated for by increased insulin secretion..
These changes persisted for up to 5 days after restoring 9-hr sleep opportunities.
The authors also showed that shifting circadian rhythm resulted in morning wakefulness and eating during the biological night, a factor that may promote weight gain over time.