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.
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.
Changes in caloric balance are long known to affect metabolic requirements – in general, overfeeding tends to increase metabolic rate, whereas underfeeding (or fasting) tends to lower metabolic rate. However, the magnitude of these changes tend to vary substantially between individuals.
Now a study by Martin Reinhardt and colleagues, published in the International Journal of Obesity, shows that this variation in response to overfeeding and fasting may predispose some individuals to obesity (thrifty phenotype).
Firstly, the researchers found that a greater %EE decrease with fasting correlated with a smaller %EE increase with overfeeding, or in other words, individuals who responded with a greater decrease in caloric expenditure in response to fasting also showed a lower increase in caloric expenditure with overfeeding.
The %EE decrease with fasting was associated with both fat mass and abdominal fat mass as well as a lower 24-hour core body temperature (even after accounting for a number of covariates). A 0.1°C lower core body temperature was associated with a 1.4% greater decrease in EE during fasting.
From these findings the authors conclude that,
“body temperature may be a further defining feature of the human thrifty phenotype and offer insight into contributors to the inter-individual variation observed in energy expenditure responses to caloric restriction or excess.”
They also suggest that perhaps careful measurements of body core temperature could be harnessed to direct weight loss or weight maintenance efforts during life style interventions.
If nothing else, the study nicely documents that we are not all equal when it comes to how our bodies respond to over or underfeeding.
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Do Variations in Breast Milk Composition Account for the Conflicting Evidence Regarding Its Protective Effects On Excess Weight Gain?
As father of three nursing mothers, I am all for breast feeding. Indeed, in several previous posts, I have cited the epidemiological data to suggest that breast feeding may be protective against childhood obesity.
However, this data is far from clear. There are in fact many conflicting studies on this issue, as a result of which breast feeding as protection for weight gain was presented as one of the “obesity myths” in a recent paper in the New England Journal of Medicine.
Now, a study by Tanya Alderete and colleagues from the university of Southern California, Los Angeles, published in the American Journal of Clinical Nutrition, suggests that the variable reports on the role of breast feeding in protecting against excess weight may be related to variations in its composition.
The researchers studied the composition of human milk oligosaccharides (HMOs) in 25 mothers and correlated these to with infant growth and body composition at 1 and 6 mo of age.
As the authors discuss, diversity and HMO composition of breast milk appeared to have disparate effects on body composition and body weight.
Thus, for example, each 1-μg/mL increase in levels of lacto-N-fucopentaose (LNFP) I was associated with an approximately 1 lb lower infant weight at 1 month and a 1.11-kg lower weight with am 0.85-g lower lean mass and a 0.79-g lower fat mass at 6 months.
In contrast, disialyl-lacto-N-tetraose and LNFPII were associated with small but significant increases in body fat mass.
Overall, these effects are not trivial,
“When examined collectively, LNFPI, DSLNT, and FDSLNH explained 33% more of the variance in infant fat mass than did sex, prepregnancy BMI, weight gain during pregnancy, and 6-mo infant age alone.”
As one potential mechanism, the authors suggest that different HMO’s may have differential effects on gut bacteria in these infants.
“HMOs are thought to aid in the growth and metabolic efficacy of the developing infant micro biome…Although we did not collect stool samples, preliminary findings observed in the current study may be partially attributed to the prebiotic effects of HMOs. In support of this, a recent study found a distinct fecal microbiota composition in breastfed compared with formula-fed infants, in which the fecal microbiota in breastfed infants correlated with the HMOs consumed (particularly LNFPI and DSLNT).”
Whatever the mechanism, as the authors note,
“These findings support the hypothesis that differences in HMO composition in mother’s milk are associated with infant growth and body composition.”
Obviously, these kind of studies cannot prove causality nor do they provide definite mechanistic insights.
However, they may open an avenue to better understanding why the literature is so conflicted when it comes to the relationship between breastfeeding and excess weight gain.
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This is largely, because to win a debate you need to take a biased and one-sided view of the topic and speak with conviction – at least if the intention is to sway the audience.
The problem is that presenting a radical stand-point convincingly may lead the audience to believe that this is your actual position on the matter (rather than simply a role assigned to you by the organizer).
To not fall into that trap, these debates often end up with the debaters agreeing more than disagreeing.
Case in point a debate at Obesity Week, on whether or not people with obesity who are metabolically healthy should be advised to lose weight.
The pro side was represented by Mark Hamer, who essentially made the argument that truly metabolically healthy obesity (MHO) is a rather rare phenotype and will in most cases (sooner or later) progress to unhealthy obesity (UHO), so that differentiating between the two both in clinical practice and in public health recommendations to lose weight is neither practical nor necessary.
On the con side, Sam Klein argued that on the one hand, MHO individuals appear far more resistant to developing metabolic risk factors (even with weight gain) and that weight-loss always comes with a cost and that interventions should therefore be focussed on people who stand to benefit the most, i.e. people who already have metabolic problems.
Klein also pointed out that we not be tempted to treat “hyperBMIemia” – but take the actual health of the patient into account.
In the end, as expected, the debaters came to agree on the fact that everyone could stand to benefit from improving their “lifestyles”, particularly their activity levels (which really wan’t the question that was being debated).
If nothing else, the debate revealed the ongoing conflict between population messages (every one should strive for a “healthy” weight – whatever that is) and clinical decision making, where recommendations need to be personalized to the actual risk of the individual.