Wednesday, December 3, 2014

Does Your Liver Control Your Appetite?

Fatty Liver

Fatty Liver

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.

@DrSharma
Edmonton, AB

ResearchBlogging.orgLópez-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

 

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Tuesday, December 2, 2014

Does Maternal Obesity Affect the Gut Microbiome of the Offspring?

sharma-obesity-gut-buts1Yesterday, I blogged about the Maternal Resource Hypothesis, proposed by Edward Archer, as a driver of childhood obesity.

Today’s post is about another interesting finding by Jeffrey Galley and colleagues from Ohio State University, published in PLOS one, suggesting that maternal obesity may be associated with differences in the gut microbiome in children in early life.

The researchers compared the gut bugs from fecal samples from children 18–27 months of age (n = 77) born to obese or non-obese mothers.

At least in women of higher socioeconomic status, offspring of obese mothers showed significant differences in their gut bacteriome from those of non-obese mothers in a manner that has been previously linked to differences in weight and diet (differences were noted in the abundances of Faecalibacterium spp., Eubacterium spp., Oscillibacter spp., and Blautia spp).

While these findings were limited to women of higher socioeconomic status, the authors do not have a ready explanation for these findings.

Their best guess is that perhaps the etiology of obesity may differ between women of higher and lower socioeconomic status and it may well be that the extent to which maternal obesity confers measureable changes to the gut microbiome of offspring may differ based on the etiology of maternal obesity.

It is unlikely that dietary differences explain these findings:

“In our sample, we found no differences in the children from obese and non-obese mothers in terms of breastfeeding behavior, age at which solid foods were introduced, or the current frequency of consumption of meat, vegetables, and cereals/grains regardless of maternal SES. This suggests that diet did not explain the observed differences in the children’s gut microbiome related to maternal obesity and SES.”

Indeed, the authors are quick to point out that further research is needed to better understand the relevance of the observed differences in gut microbiome composition for weight trajectory over the life course of the offspring:

The potential role of the gut microbiome in this intergenerational transmission of obesity risk warrants further attention. In particular, the stability of such effects into later childhood and adolescence, the clinical relevance of abundances of specific bacteria in conferring risk for obesity, and the ultimate impact of early life microbial profiles on long-term weight trajectory remains to be explicated.”

Nevertheless, these findings are intriguing in that they suggest a link between maternal obesity and the possible transmission of obesogenic microbes to their offspring.

@DrSharma
Vancouver, BC

ResearchBlogging.orgGalley JD, Bailey M, Kamp Dush C, Schoppe-Sullivan S, & Christian LM (2014). Maternal obesity is associated with alterations in the gut microbiome in toddlers. PloS one, 9 (11) PMID: 25409177

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Monday, December 1, 2014

Are Sedentary Moms Promoting Childhood Obesity?

Edward Archer, PhD, University of Alabama Birmingham

Edward Archer, PhD, University of Alabama Birmingham

Last week, Edward Archer from the University of Alabama at Birmingham (UAB), published a paper in the Mayo Clinic Proceedings (to much media fanfare), suggesting that the primary driver of childhood obesity is the shifting of nutrient energy to fetal adipose tissue as a result of increased maternal energy availability paired with decreased maternal energy expenditure, resulting in fetal pancreatic b-cell and adipocyte hyperplasia – a theory, which Edwards labels the “maternal resource hypothesis”.

The primary process for these changes, as readers of these pages will have read before, is through epigenetic modification of DNA, which, together with other non-genetic modes of transmission including learned behaviours and environmental exposures (socioenvironmental evolution), leads to “phenotypic evolution”, which Edward describes as,

“…a unidirectional, progressive alteration in ontogeny that is propagated over multiple successive generations and may be quantified as the change over time in the population mean for the trait under examination (eg, height and obesity).”

Since the beginning of the 20th century, socioevironmental factors have significantly altered the energy balance equation for humans

“Socioenvironmental evolution has altered the evolution of human energy metabolism by inducing substantial decrements in EE imposed by daily life while improving both the quality and the quantity of nutrient-energy availability.”

“For example, as thermoneutral environments became ubiquitous, the energy cost of thermoregulation declined, and improved sanitation (eg, clean water and safer food) and vaccinations decreased the energy cost of supporting parasites (eg, fleas) and resisting pathogens (eg, communicable diseases and diarrheal infections).”

Over the past century, these developments have led to profound phenotypic changes including,

“progressive and cumulative increases in height, body stature and mass, birthweight, organ mass, head circumference, fat mass/adiposity as well as decreases in the age at which adolescents attain sexual maturity…”

Archer goes on to describe some of the many factors that may have changed in the past century, whereby, he singles out sedentariness as one of the key drivers of these developments (not surprising given Archer’s background in exercise science).

Thus, although one could perhaps make very similar arguments for any number of factor that may have changed in the past century to, in turn, affect insulin resistance and ultimately energy partitioning (change in diet, sleep deprivation, increasing maternal age, endocrine disruptors, antibiotic use, gut microbiota, medication use and many other factors I ca think of), Archer chooses to elevate sedentariness to being the main culprit.

While this may or may not be the full story, it does not change the thrust of the paper, which implies that we need to look for the key drivers of childhood obesity in the changes to the maternal-fetal (and early childhood) environment that have put us on this self-perpetuating unidirectional cycle of phenotypic evolution.

Ergo, the solution lies in focussing on the health behaviours (again, Archer emphasizes the role of physical activity) of moms.

While Archer largely focusses on maternal transmission, we should perhaps not forget that there is now some also evidence implicating a role for epigenetic modification and intergenerational transmission through paternal DNA – yes, dads are getting older and more sedentary too (not to mention fatter).

I do however agree with Edward, that this line of thinking may well have important implications for how we approach this epidemic.

For one,

“…the acknowledgment that obesity is the result of non-genetic evolutionary forces and not gluttony and sloth may help to alter the moralizing and demoralizing social and scientific discourse that pervades both public and clinical settings.”

Secondly,

“Future research may be most productive if funding is directed away from naive examinations of energy balance per se and redirected to investigations of interventions that alter the competitive strategies of various tissues.”

Thirdly,

“From the standpoint of the clinician, accurate patient phenotyping (inclusive of family obstetric history and metabolic profiling) may allow the targeting of women most likely to be a part of populations that have evolved beyond the metabolic tipping point and therefore require significant preconception intervention.”

While none of this may be easier or more feasible than other current efforts, they may well point us in a different direction than conventional theories about what is driving childhood obesity.

@DrSharma
Calgary, AB

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Monday, November 24, 2014

Obesity Myth: Anyone Can Lose Weight

scaleHere is another common misconception about obesity discussed in our article in Canadian Family Physician:

“It is common to hear that weight loss is a matter of willpower and compliance with the weight-reducing program.

However, the magnitude of weight loss is very different among individuals with the same weight-loss intervention and prescription, and the same compliance to the program—one size does not fit all.

Thus, for some people (especially those who have already lost some weight), simply putting more effort into a weight-loss program will not always result in additional weight loss given the different compensatory adaptations to weight loss.

For example, the decrease in energy expenditure that occurs during weight loss is highly variable between people and might dampen efforts to lose additional body fat.

Such compensatory mechanisms might sometimes fully counteract the 500 kcal per day decrease recommended in most dietary interventions, making it very difficult for such “poor responders” to lose weight.

Physicians should remember that obesity is not a choice and weight-loss success is different for every patient.

Success can be defined as better quality of life, greater self-esteem, higher energy levels, improved overall health, or the prevention of further weight gain.”

@DrSharma
Edmonton, AB

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Thursday, November 20, 2014

Obesity Myth: Losing Weight Is Always Beneficial For Your Health

sharma-obesity-scale2Another common misconception about obesity discusses in our recent paper in Canadian Family Medicine, is the notion that anyone with excess weight stands to benefit from losing weight.

The benefits of weight loss, however are far from as established as most of us may think:

“The strong biological response to weight loss (even the recommended 5% to 10% of baseline weight) involves comprehensive, persistent, and redundant adaptations in energy homeostasis that underlie the high recidivism rate of obesity treatment.

The multiple systems regulating energy stores and opposing the maintenance of a reduced body weight illustrate that fat stores are actively defended.

Among the adverse effects of weight loss, it is well known that body fat loss increases the drive to eat, reduces energy expenditure to a greater extent than predicted, and increases the tendency toward hypoglycemia.

Weight loss is also related to psychological stress, increased risk of depressive symptoms, and increased levels of persistent organic pollutants that promote hormone disruption and metabolic complications, all of which are adaptations that substantially increase the risk of weight regain.

In addition, there is considerable concern about the negative effect of “failed” weight-loss attempts on self-esteem, body image, and mental health.

Thus, clinicians should document and consider the powerful biological counter-regulatory responses and potential undesired effects of weight loss to maximize the success of their interventions. Obesity is a chronic condition and its management requires realistic and sustainable treatment strategies.

Successful obesity management requires identifying and addressing the obesity drivers as well as the barriers to and potential complications of weight management. Family physicians should discuss the possible adverse effects of weight loss with their patients and actively look for these effects in patients trying to lose weight.”

@DrSharma
Wellington, NZ

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In The News

Diabetics in most need of bariatric surgery, university study finds

Oct. 18, 2013 – Ottawa Citizen: "Encouraging more men to consider bariatric surgery is also important, since it's the best treatment and can stop diabetic patients from needing insulin, said Dr. Arya Sharma, chair in obesity research and management at the University of Alberta." Read article

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