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.
The speaker series was hosted by the principal of the college,the Right Honourable Kim Campbell, who served as Canada’s 19th prime minister in 1993.
While I spoke about the particular challenges and barriers faced by Canadians living with obesity and how these can be accommodated and supported in the workplace and society in general, other speakers spoke on the accommodation of individuals living with other challenges.
Thus, Kelly Falardeau, herself a victim and advocate for burn survivors and Deryk Beal, one of Canada’s leading clinician scientists on stuttering and other speech impediments, joined me in speaking on the importance of diversity and the need to identify obstacles to social inclusion that keep individuals from reaching their full potential.
In my presentation I did my best to portray the biological, physical, emotional and societal challenges that Canadians living with obesity face everyday.
Here is what I asked the students to think about:
“So how can we help people living with such barriers?
For one, let us educate ourselves on the real issues – if there was an easy solution that actually worked, believe me my clinic would be empty.
Secondly, let us show some respect for people who wake up with this barrier every single morning and go through their day – for the most part doing everything everyone else does.
Thirdly, let us acknowledge that once you have obesity there is no easy way back. I have patients who have lost their entire weight over on diet after diet after diet only to put the weight back again. Diet and exercise is simply not enough for most people – surgery works but is not available and not scalable – we cannot do surgery on 120,000 Albertans. So let us not pretend that there is an easy solution to the problem – we simply don’t have enough treatments that work.
Fourthly, till we do come up with more treatments that actually work or maybe even get our act together on prevention, let us not make life harder for people living with this barrier than it has to be. We can do many things to accommodate people living with obesity – we accommodate people with all kinds of “special needs” at home, in society in the workplace – just not for people living with obesity.
Fifth, let us show our support for people who struggle with their weight by the way we treat them, the way we talk about them, the way we engage with them – they are people like all of us. Just because they carry extra weight does not mean they are second class citizens or people we can simply make fun of or ignore – we are after all talking about 7 million Canadians – men, women and children.
Let us not be the barrier that makes their life even more difficult than it already is.”
Our presentations were followed by an enthusiastic ‘master class’ with students in the inaugural leadership class of the Peter Lougheed Leadership College.
I’d like to thank the organizers for giving me the opportunity to advocate on behalf of Canadians living with obesity.
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.
Neuroimaging studies have implicated the left dorsolateral prefrontal cortex (LDLPFC), an area of the brain that plays an important role in the organization and planning of behavior including goal-oriented regulation of eating behavior and food choice, has been implicated in obesity.
Now Marci Gluck and colleagues, present a proof of concept study published in OBESITY, suggesting that effects of cathodal transcranial direct current stimulation (tDCS)aimed at the LDLPFC may reduce energy intake and promote weight loss in individuals with obesity.
The randomised sham-controlled study was conducted in 9 (3m, 6f) healthy volunteers with obesity, who were admitted as inpatients for 9 days to a metabolic ward.
In a first study, following 5 days of a weight-maintaining diet, participants received cathodal or sham tDCS (2 mA, 40 min) on three consecutive mornings and then ate ad libitum from a computerized vending machine, which recorded energy intake.
In a second study participants repeated the 1st study, maintaining original assignment to active (this time anodal) and sham.
In both studies, each stimulation session consisted of 40 min of anodal tDCS delivered with a neuroConn® DC-STIMULATOR device, at a constant current of 2 mA (with a 30-second ramp at on- and offset) using two 5 × 5 cm sponge electrodes soaked in a sterile 0.9% sodium chloride solution.
Participants who received active tDCS consumed about 700 fewer total kilocalories per day during anodal versus cathodal stimulation. This reduction in caloric intake was mainly a result of reduced fat and pop consumption.
In contrast, sham stimulation had no effect on energy intake.
As may be expected in this short term study, not much happened to body weight.
Regarding the mechanisms the authors speculate that,
“Our results, in combination with previous work, point to a role for the LDLPFC in energy intake and body weight regulation. However, the mechanisms that mediate this association are not clear. Capacity for self-control in reward-related decision-making tasks depends critically on the activity of the DLPFC, a region that is activated in response to cues that induce food craving…. Thus, anodal tDCS over the LDLPFC could have reduced food intake by simultaneously suppressing food cravings and facilitating choices requiring delayed gratification.”
As the authors optimistically conclude,
“In this proof of principle clinical trial, participants with obesity receiving anodal versus cathodal tDCS to the LDLPFC tended to have lower ad libitum energy intake, less fat and soda intake, and significant differences in weight change. “
Obviously, it will take longer term studies as well as further exploration of the type of patient who may benefit from this type of treatment, before we can judge whether this type of treatment (which appears to be otherwise safe) can play a role in obesity management.
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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