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Does Cannabis Use Protect Against Obesity And Diabetes?

sharma-obesity-cannabis_leaf3Anyone even remotely familiar with cannabis use and its potential to cause the “munchies” would immediately assume that regular cannabis use would likely promote weight gain and, in consequence, the risk forf type 2 diabetes.

Thus, readers may well be as intrigued as I am by the work of Gerard Ngueta and colleagues from Québec, Canada, published in OBESITY, showing a rather strong inverse association between cannabis use and BMI in the Inuit.

The researchers analyzed data from 786 Inuit adults from the Nunavik Inuit Health Survey (2004), which included self-reported use of cannabis as well as measured levels of fasting blood glucose and insulin.

Not only was cannabis use highly prevalent in the study population (57%), but even after adjustment for a number of potential confounders, cannabis use was significantly associated with lower body mass index (BMI) (about 2 BMI points, P < 0.001), lower % fat mass (P < 0.001), lower fasting insulin (P = 0.04), and lower HOMA-IR (P = 0.01).

In multivariate analysis, past-year cannabis use was associated with 0.56 lower likelihood of obesity (95% confidence interval 0.37-0.84), and it was this relationship that fully explained the seemingly positive effect of cannabis use on insulin resistance (as a surrogate for diabetes risk).

It may also be worth noting that the association of cannabis use with lower BMI was only seen in past or non-smokers, but not in current tobacco smokers.

Now normally, being highly sceptical of these types of association studies, which are generally hopelessly confounded and can never prove causality, I would have dismissed this as a chance finding  of little significance.

Imagine my surprise, however, when the authors go on to mention several previous studies, in a variety of populations, that have reported similar findings.

Unfortunately, the authors have little to offer in terms of a plausible biological mechanism and can only speculate on possible genetic or functional factors involving the cannabinoid system or putative effects on energy expenditure associated with the pulmonary consequences of smoking.

Thus, I can presently make little of this finding – but I will likely stay tuned.

@DrSharma,
Edmonton, AB

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How the FTO Gene Contributes to Obesity

sharma-obesity-dna_molecule9While I took a month off from blogging, an international group of researchers published what may well become a landmark paper on the genetics of obesity in the New England Journal of Medicine.

As regular readers may be well aware, a number of previous genetic studies have pointed to the importance of the FTO gene for human obesity – however, what exactly this gene does to effect body weight was largely unclear.

The rs1421085 single-nucleotide variant of this gene has both a high frequency and a strong effect size, which suggests positive selection or bottlenecks (e.g., 44% frequency in European populations vs. 5% in African populations).

In the present paper, that included examination of epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns in mice and humans, the researchers showed that the FTO allele associated with obesity represses mitochondrial energy production in adipocyte precursor cells in a tissue-autonomous manner.

To be precise, the rs1421085 variant of this gene apparently disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. These molecules play key roles in thermogenic dissipation both through UCP-1 and UCP-1-independent pathways.

This change leads to a persistent and cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5. It is also associated with an increase in lipid storage and adipocyte cell size.

Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite.

Knockdown of IRX3 or IRX5 in primary adipocytes from human subjects with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers.

 

Finally, repair of the ARID5B motif in primary cultured adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7.

These deep insights into the function of what is apparently a key pathway in human susceptibility (or resistance) to obesity, offers a number of potential targets for pharmacological interventions for obesity – something that we desperately need for patients struggling with this issue.

However, as an accompanying editorial is quick to point out,

“As yet, there is still no simple path to an anti-obesity drug that can be derived from this research.”

Then again, who expects finding new treatments for obesity to be simple?

@DrSharma
Edmonton, AB

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Obesity Down Under

Standing in the rain with Professor Joseph Proietto, Melbourne, Australia

Standing in the rain with Professor Joseph Proietto, Melbourne, Australia

Following a rather relaxed August, which included meeting my new grand daughter and turning my attention to jazz guitar, I spent the last week in Australia speaking at the Australian Diabetes and Diabetes Educator conference in Adelaide and visiting colleagues at the Melbourne Baker Institute and Sydney University’s Charles Perkins Centre.

Clearly, Australia has an obesity problem that easily rivals that of most “western” countries, with no real solutions in sight (as in most “western” countries).

As virtually everywhere else, much government talk (and millions of dollars) focusses on prevention, while access to obesity management within the healthcare system (public or private) remains as sparse and unfunded as everywhere else.

Whilst other countries are gradually grappling with the idea that obesity, once established, must be considered a chronic disease (and thus requires the same approach to management as any other chronic disease), it appears that government and professional agencies in Australia are particularly resistant to accepting this reality.

This is especially surprising, as some of the best and strongest evidence for the chronicity of obesity and the complex biological responses that occur to defend against weight loss and virtually guarantee weight regain (including studies published in the New England Journal of Medicine and the Lancet),  come from my colleague Joe Proietto’s group Down Under.

I guess the fact that even the best science rarely translates into effective policies is not just a problem in Canada.

@DrSharma
Sydney, Australia

 

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Time For A Bloggation

taylor guitarAs in the last couple of years, I am taking August off from blogging – will spend the extra time playing my guitar and visiting the grandkids.

For the diehards – feel free to flip through the 2000+ past posts – many are as relevant today as the day they were written.

Hope you have a great Summer – see you in Sept.

@DrSharma
Edmonton, AB

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Why Treating Severe Obesity Has The Highest Potential For Health Cost Savings

sharma-obesity-dollarsAs the latest HQCA report on obesity in Alberta released this week, the substantial population burden of overweight and obesity (now affecting 6 in 10 Albertans) is a significant driver of health care costs in the province. In the US, this increased health care cost for adult obesity is estimated at around $3,508 per individual with a BMI greater than 30 for a total of well over US$ 300 billion per year.

However, as highlighted in a recent article by John Cawley and colleagues in PharmacoEconomics, health care costs are not equally distributed across all people living with increased body weight – rather, obesity related health care costs rise exponentially with increasing BMI levels (i.e. at the extremes of BMI).

Thus, the greatest health care savings for individual patients can be expected in those living with severe obesity.

To illustrate this, the researchers used data from the US Medical Expenditure Panel Survey from 2000-2010 (n=41,435), to calculate the potential annual savings in health care costs (in US $ in the US health care system), for various reductions in body weight in individuals with BMI levels ranging from 30 kg/m2 to 45 kg/m2.

Thus, for e.g. the annual cost savings with a 5% reduction in body weight for someone with a BMI of 30 kg/m2 amounted to a mere $69 per year.

This figure, however, increased exponentially for people with higher BMIs, increasing to $528, $2,137, and $10,030 in an individual with a BMI of 35, 40, and 45 kg/m2, respectively (these figures were somewhat higher, when the individual also has diabetes).

Thus, while treating obesity to achieve a 5% reduction in body weight in someone with a BMI of 30 kg/m2 may never be “cost-effective”, the same amount of weight loss in someone with more extreme obesity, would likely pay for itself or even lead to significant savings.

Because the impact of obesity on mental and physical health, life-expectancy and quality of life is also greatest at higher levels of BMI, one could also make a strong ethical argument for singling out these individuals for priority treatment in the health care system.

Obviously, as readers should be aware, BMI is at best a crude measure for health – a more precise assessment would have used more sophisticated staging systems like the Edmonton Obesity Staging System to calculate individual risk and benefits. However, we should remember that at a population level BMI does function moderately well as an indicator of obesity related risk (although not in individual patients).

This analysis has important consequences both for population and individuals approaches to obesity.

Although the population burden of obesity lies in the middle of the BMI bell curve, and shifting this ever so slightly can move a substantial number of people living with overweight or obesity to a BMI that lies below the current cut-offs, such a change may have little influence on the overall health care costs of obesity, as these live in the extremes.

Thus, using the above numbers in a crude back-of-the-envelope calculation, to save $1,000,0000 per year in health care costs, one would have to lower BMI by 5% in about 14,500 people living with a BMI of 30 kg/m2 compared to only 100 people with a BMI of 45 kg/m2 – a much more manageable problem.

This is why it is harder to make a cost-savings argument for addressing obesity at a population level rather than focussing on those living with more severe obesity, unless such population measures can also substantially help lower the BMI of the latter.

Unfortunately, current population trends show that while rates of overweight and mild obesity appear to be levelling off (thank perhaps in part to population health measures), severe obesity continues to increase at alarming rates.

This is why a greater focus on finding and delivering better treatments to those living with severe obesity, including those that can only offer modest reductions in BMI, has to be the main priority of any health care system seeking to reduce obesity related health care costs.

@DrSharma
Edmonton, AB

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Overweight And Obesity In Alberta; A Role For Primary Care

HQCA_Obesity_Info_graphic712x1160Yesterday, the Health Quality Council of Alberta, released a report called Overweight and obesity in adult Albertans: a role for primary healthcare, which provides an in-depth analysis of the prevalence, burden, and rates of use of a number of key healthcare services for overweight and obese individuals in Alberta. The report also provides a strong rationale for the role of primary healthcare in weight management for adult Albertans living with overweight and obesity.

In 2014, the HQCA conducted a survey of adult Albertans about their use and satisfaction with healthcare services. As part of this survey, self-reported height and weight were collected from individuals in order to calculate their body mass index. According to these findings, nearly six out of 10 Albertans over the age of 18 were either overweight or obese. The estimated provincial prevalence of adults with overweight and obesity was 35.2 per cent and 23.9 per cent, respectively. In addition, obesity was associated with an increased risk of multiple comorbidities, greater use of healthcare system services, and a lower self-rated individual quality of life.

Managing overweight and obese populations, as well as comorbid conditions, falls predominantly on primary healthcare providers. Evidence shows that diverse strategies for the management of overweight and obesity within primary healthcare are associated with benefits in weight management; however, the most effective mix of providers, interventions, and duration requires further evaluation. Moving forward, Alberta may benefit from working towards a more unified strategy for weight management that includes opportunities to engage Albertans in discussions about weight management, and to increase the use of team-based care across all weight categories.

The full report is available here.

A fact sheet is available here.

@DrSharma
Edmonton, Alberta

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What Are The Health Benefits of Intentional Weight Loss?

sharma-obesity-weight-gainTo conclude this brief series on our new exhaustive review of the putative health benefits of long-term weight-loss maintenance, published in Annual Reviews of Nutrition, here is the summary paragraph of our findings:

“Obesity is well recognized as a risk factor for a wide range of health issues affecting virtually every organ system. There is now considerable evidence that intentional weight loss is associated with clinically relevant benefits for the majority of these health issues. However, the degree of weight loss that must be achieved and sustained to reap these benefits varies widely between comorbidities. Downsides of weight loss that is too rapid and/or extreme may occur, as in the increased risk of gallbladder disease, the presence of excess residual skin, or deterioration in liver histology. Uncertainty also remains about the potential benefit or harm of intentional weight loss on patients presenting with some chronic diseases and on overall mortality. Clearly, well- controlled prospective studies are needed to better understand the natural history of obesity and the impact of weight-management interventions on morbidity, quality of life, and mortality in people living with obesity.”

The is much left to be done and answering some of these questions will become progressively easier as better treatments for obesity become available.

@DrSharma
Kananaskis

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What We Do Not Know About Weight Loss

Controversies in ObesityIn our exhaustive review of the potential health benefits of intentional long-term weight loss, published in Annual Reviews in Nutrition, I discussed in yesterday’s post, we also noted a number of issues that remain unresolved.

These include:

  1. The precise definition of success in terms of weight loss remains controversial, and the dogmatic assumption that prolonged periods of sustained weight loss (greater than 10 years) are more likely than shorter periods to have a beneficial effect on health out- comes has never been challenged.
  2. Some evidence suggests that intentional weight loss may lead to meaningful reductions in several conditions, such as COPD, and cancer risk with a short latency time, although data from randomized trials are not yet available to support this hypothesis.
  3. Future studies on the relationship between long-term weight loss and suicide are needed, especially in diverse populations, subgroups of patients, and those who engage in other long-term weight-loss strategies apart from the use of antiobesity medications and bariatric surgery. The potential relationship between failed weight-loss attempts and suicide ideation needs to be evaluated.
  4. There is ongoing controversy over the findings from epidemiological studies on the relationship between weight loss and mortality. Data from controlled studies in this regard are very limited.

Clearly, as we discussed at length here at the ongoing Canadian Obesity Network’s Obesity Research Summer School (Boot camp), much remains to be done for young researchers planning a career in this field.

@DrSharma
Kananaskis, AB

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