Richard Lehner

New findings published by University of Alberta researchers in a recent issue of Cell Metabolism may point to a new pharmacological target for reducing fat and blood sugar levels in blood while also positively affecting energy expenditure (at least in mice).

The research team, led by Richard Lehner (picture), showed that genetically knocking out an enzyme called TGH (triacylglycerol hydrolase), which is normally involved in helping the liver (and other tissues) process fat, not only reduces blood fat levels but also improves insulin sensitivity and glucose tolerance.

Interestingly, the animals were also better able to utilize glucose and, despite consuming significantly more energy, they displayed increased locomotor activity and consequently did not gain weight.

As always, such studies in mice must be taken with a grain of salt in that there is usually a long way to go before (if at all) these findings pan out in new treatments for humans.

On the other hand, these studies do demonstrate the potential of TGH as a therapeutic target for lowering blood lipid levels and possibly body weight through a novel pathway.

AMS
Munich, Germany

One of the most common notions of why obesity is so rampant today is because most of us carry in us the genetic ability to avidly take up calories when they are around and use them sparingly when they are not.

This notion has been called the “thrify genotype” and has been credited with allowing our ancestors to make it through the millenia of feasts and famines, while being blamed for the obesity epidemic today.

But does the genetic ability to become fat really bestow a survival advantage?

This question was addressed by David Pierce and colleagues from the University of Alberta in a paper just published in the International Journal of Obesity.

In this study, young genetically obese and lean-prone rats were exposed to a rigorous regimen of sparce food and ample exercise (wheel running).

Although the obese and lean-prone rats started out at the the same initial body weight, the obese-prone rats survived twice as long, and ran three times as far, as their lean-prone counterparts.

In addition, the obese-prone animals were able to maintain blood glucose and fat mass, whereas lean-prone rats quickly depleted these energy reserves. Judging by the corticosterone concentrations, the obese-prone rats appeared far less stressed by the survival challenge than their lean-prone counterparts.

This study clearly demonstrates that (at least in rats), carrying the genes for obesity confers a huge survival advantage during severe food restriction and strenuous exercise. In fact, even unders these “thrifty” conditions, the obesity prone animals were able to conserve their fat mass by being far more efficient (energetically) than their lean counterparts (same amount of work for fewer calories).

Thus, these findings not only support the hypothesis that an obese-prone genotype provides a substantial fitness advantage when the going gets tough but also shows why the same amount of dieting and exercising simply does not lead to the same amount of weight loss for everyone.

I guess it’s clear who the survivors of the next famine will be…

AMS
Edmonton, Alberta

While there is no doubt that our current obesogenic environment is the major driver of the obesity epidemic there is also no doubt that these environmental factors don’t affect everyone to the same degree. Indeed, there is now largely consensus amongst experts that the question of who will get obese and who won’t, given that we are all more or less exposed to the same environmental pressures, is largely determined by our genetic make up (yes, genes also influence behaviour!).

This is even more true for those individuals who make up the rapidly growing group of people with severe obesity - anyone, who believes that you can get to weighing over 350 lbs or more simply by making wrong “choices” probably also still believes in Santa Claus and can’t wait for the Easter Bunny.

Yesterday, the journal Nature reported another study that shows how genetic mutations can markedly increase the risk for severe obesity.

In this large multicentre study headed by my friend and colleague Philippe Froguel, the investigators found a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of a surprisingly large area of chromosome 16 (593 kilobases at 16p11.2) and who also presented with some cognitive deficits.

Subsequently, they identified 19 similar deletions in genome wide association data in 16,053 individuals from eight European cohorts. None of these deletions were found in healthy non-obese controls and were estimated to account for 0.7% of the morbid obesity cases in the dataset.

Interestingly, the parents of some of these index cases also had this deletion and were likewise obese. The cases with the deletion tended to be born with a normal weight but then became overweight at childhood and severely obese as adults.

Unfortunately, this large stretch of chromosome 16 contains many different genes (as many as 30) and it is not clear from these studies exactly which or how these missing genes contribute to the severe obesity phenotype.

Nevertheless, given that this is neither the first genetic defect to be associated with severe obesity nor likely to be the last one of what is believed to be a relatively large number of genetic mutations that have yet to be found, this report should come as a strong warning to anyone who believes that severe obesity is solely a self-inflicted condition resulting purely from poor “choices”.

AMS
Copenhagen, Denmark

As obesity is widely believed to be a condition resulting from people’s poor lifestyle choices, it is only normal to also believe that childhood obesity is simply the result of poor parenting skills. Thus, in severe cases, childhood obesity has been likened to childhood abuse and there are cases where obese children have been brought to the attention of social services and child protection agencies.

As now reported by the BBC, at least a few such parents have recently been exonerated after the discovery that the severe obesity that resulted in their children being formally placed on the social services ‘at risk’ register on the assumption that the parents were deliberately overfeeding the kids, were removed from the register after the discovery of a new genetic defect that largely explained the kids’ excess weight.

This new genetic defect, consisting of large chromosomal deletions associated with severe early-onset obesity, was reported by Elena Bochukova and colleagues from the University of Cambridge, UK, in an early online publication in NATURE.

In their study of 300 Caucasian patients with severe early-onset obesity, 143 of whom also had developmental delay, the researchers identified several rare copy number variants that were recurrent in patients but absent or at much lower prevalence in controls.

Five patients had overlapping deletions on chromosome 16. Two patients harboured a larger de novo chromosome 16 deletion, extending through a 593-kilobase region previously associated with autism and mental retardation. In an independent sample of 1,062 patients with severe obesity, the smaller chromosome 16 deletion was found in an additional two patients. All deletions include SH2B1, which is involved in leptin and insulin signaling.

All deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity.

Not only does this study point to an important role of this region of chromosome 16 (and possibly SH2B1) for rare cases of early-onset hyperphagic obesity, but it also shows that even genetic obesity is a remarkably heterogeneous disorder.

This study certainly serves as a reminder that jumping to conclusions about peoples lifestyle “choices” based simply on their appearance is never a good idea.

AMS
Edmonton, Alberta

Body weight is one of the most highly regulated genetic traits.

This is perhaps best demonstrated by the fact that it is almost impossible to find genetically identical individuals (or monozygotic twins) with marked differences in body weight.

In contrast, it is much easier to find non-identical twins (who only share some of their genes but the same environment) with great differences in body weight.

Despite this strong influence of genes on body weight, lifestyle can very much make a difference.

This was now demonstrated by Tuija Leskinen and colleagues from the University of Jyväskylä, Finland, who after combing through thousands of twin pairs from the Finnish Twin Cohort, identified seven genetically identical (monozygotic) and nine non-identical (dizygotic) middle-aged (50-74 years) same-sex twin pairs who reported a long-term discordance for physical activity (International Journal of Obesity).

Irrespective of the genetic make up, the physically inactive co-twins had a 50% greater visceral fat area, a 170% higher liver fat score, and 54% more intramuscular fat.

This study clearly demonstrates that even in individuals who share the same genes and/or similar childhood environments, regular physical exercise can prevent the accumulation of high-risk fat over time.

Thus, whatever your genetic background or early childhood environment, it is better to be regularly physically active than sedentary (who would have guessed?).

AMS
Edmonton, Alberta