Arya M. Sharma, MD

Continuing my posts on the recent articles on obesity and mental health published in the January issue of the Canadian Journal of Psychiatry, I now turn my attention to a paper by Valerie Taylor and colleagues on the many links between mental health issues and obesity.

Whilst in the previous post I have focussed on the relationship between psychiatric medications and weight gain, a problem that is common knowledge to the mental health community, this article highlights many of the lesser known links between mental health problems and excess weight. These include interesting neurobiological, psychological, and sociological factors, that are now increasingly understood.

For e.g.

“‘Atypical’ depression, a type of major depressive disorder characterized by an increase in the need for sleep and food, may actually characterize the most ‘typical’ presentation of major depression For the majority of people with depression, therefore, a diagnosis of major depression is synonymous with a phenotype that increases vulnerability towards weight problems.”

In fact,

“The neurobiology of depression [also] confers increased risk of obesity. The most common biological perturbation associated with depression is an increase in cortisol. This increase, and the hypothalamic pituitary adrenal axis abnormalities that accompany it, is similar to changes seen in Cushing syndrome, an endocrinological illness caused by an increase in cortisol that is characterized phenotypically by excessive visceral weight gain. While levels of cortisol found in major depression disorders are much lower than that of Cushings, the biological impact of excess cortisol is similar; a predisposition towards increased deposition of centrally located adipose tissue.”

In addition mood disorders often affect sleeping behaviour, which in turn affects important regulators of appetite and metabolism like ghrelin, leptin, adiponectin, and other hormones. Moreover, chronic inflammation may play a role in both major depression and obesity.

In the case of schizophrenia, primary negative symptoms like amotivation, which can be observed even in the earliest stages of the illness, may lead to reduced physical capacity and altered self-perception. Hypodopaminergic activity may in part explain increased propensity for substance use, especially cannabis, which can promote hyperphagia.

There is an increasingly recognized association between obesity and attention deficit disorder, and it may well be that impulsivity may play an important role in overeating.

Also,

“Poor planning and an inability to delay reward, processes largely mediated by the pre-frontal cortex, may lead individuals with ADHD to over-consume highly palatable, fattening foods. A related hypothesis is that individuals with low intrinsic dopamine activity in brain areas mediating reward may attempt to compensate by using various reinforcing behaviors including increased food consumption. This has been termed the “reward deficiency syndrome” and has been described separately in ADHD and in obesity suggesting that ADHD and obesity may thus reflect different manifestations of a single biological change related to low dopamine activity in prefrontal attentional areas and brain reward pathways.”

The paper also discussed findings showing that ADHD is associated with more media consumption, less participation in physical activity and organized sports.

Finally, the paper examines the literature on the relationship between obesity and childhood adverse events like sexual, mental, physical abuse and emotional neglect, which can have important impacts on the hypothalamic-pituitary-adrenal axis as well as on sex hormones that may promote fat accumulation.

“The use of food as a coping strategy or a “self-soothing behavior” is seen in both trauma patients and in those with mood disorders, and it may be related to the use of food to modulate neurotransmitters involved in affect control. Most work in this area has focused on serotonin and dopamine, both of which play a critical role in both eating behavior and mood regulation. It may be that the ability of certain foods to temporarily boost mood can create a behavioral cycle where food is consumed to control feelings of sadness.”

As readers of these posts may be well aware,

“The relationship between trauma and weight is especially evident during weight loss treatment programs and in bariatric surgery programs, a past history of trauma can be a harbinger of post-operative problems. Food and weight gain in response to abuse may be related to a desire to become “bigger” to be able to defend against an abuser, it may have been a way to change appearance when an individual inaccurately felt they were somehow provoking the abuse or it may have become a surrogate comfort mechanism when appropriate supports failed.”

Thus, clinicians (and patients) must be aware of the complex relationship between obesity and mental health issues that go well beyond just the issue of weight gain with psychiatric medications (which of course further compound these issues).

All the more reason, why all health professionals called upon to manage obesity should be well versed in recognizing and helping patients address mental health problems.

AMS
Edmonton, Alberta

Klinikum Benjamin Franklin, Charite, Berlin

Continuing in my series of past publications on obesity, today’s post is special, because it is about an event that ‘officially’ launched my shift from hypertension into obesity research and for the first time made some of the leading obesity researchers of the time aware of my very existence.

Back in 1998, I had already well-established myself in the hypertension field, being widely recognized as an expert on salt-sensitive hypertension. I was already being invited to speak at various hypertension meetings around the world and was nationally and internationally recognized for this work.

However, it would be fair to say that despite having published a few minor papers on obesity, no one in the obesity arena had ever heard of me. This was by no means surprising as, having attended a few obesity conferences by then, it was evident that few hypertension researchers interacted with obesity researchers and vice versa. Apparently, no one had yet thought of bringing the two research communities together - surprising perhaps, given the fact that obesity is the most common and powerful risk factor for hypertension.

So, perhaps for the first time demonstrating my potential talent as a ‘networker’, I decided to organize the 1st International Symposium on Obesity and Hypertension (ISOH), to which I rather cheekily ventured to invite some of the most distinguished researchers from the obesity field - cheeky, because these folks had certainly never heard of me and I was not offering any honoraria or expensive airplane tickets. I just looked for big names in obesity on the internet and sent out the invitations.

Little would I have imagined that I would assemble a roster of cutting edge ‘big names’ from both the hypertension and obesity communities for a tightly packed two day event in Berlin.

To my lay readers, the names may mean nothing, but to my professional colleagues, the following list probably reads like a ‘who-is-who’ of obesity.

W. P. T. James (Chairman, International Obesity Task Force, Aberdeen, UK) presented new data suggesting that obesity-associated comorbidity may increase rapidly in non-Caucasians with a body mass index as low as 18 kg/m2.

M. E. J. Lean (Department of Human Nutrition, University of Glasgow, UK) presented new data indicating that waist circumference (measured midway between the lowest rib and the iliac crest) is the best clinical marker of intraabdominal fat accumulation and that risks are high enough to warrant professional guidance with a waist over 102 cm in men or 88 cm in women.

R. Negrel (Centre de Biochimie, UMR6543CNRS & IFR349, Faculty of Sciences, Nice, France) and G. Löffler (University of Regensburg, Institute of Biochemistry, Regensburg, Germany), who provided convincing evidence on the presence of the renin-angiotensin system in adipose tissue.

D. L. Crandall (Wyeth Ayerst Research, Radnor, PA, USA) presented a comprehensive review, inncluding historical review of the classical experiments that identified early hemodynamic changes observed in obesity and the important role of neovascularization for the growth and development of adipose tissue.

H. Hauner (Diabetes Research Institute at the University of Düsseldorf, Germany) stressed the point that stromal cells from adipose tissue can undergo differentiation in the presence of defined adipogenic factors, including a variety of hormones and cytokines.

T. Unger (Institute for Pharmacology, Christian-Albrechts University of Kiel, Germany) presented evidence that the AT1 and AT2 angiotensin receptors may play an important role in the growth and development of a variety of tissues, including cardiac, endothelial, and neuronal cells.

F. C. Luft (Franz Volhard Clinic and Max Delbrück Center, Humboldt University of Berlin, Germany) presented the results of linkage analysis in an Arab pedigree with familial hypercholesterolemia in which heterozygous persons with normal LDL levels were identified.

T. W. Kurtz (University of California, San Francisco, CA, USA) and M. Pravenec (Czech Academy of Sciences, Prague, Czech Republic) presented data indicating that a Cd36 Mutation in some strains of spontaneously hypertensive rat may be associated with insulin resistance in these strains.

X. Jeunemaitre (INSERM U36, College de France, Paris, France) provided new evidence indicating that several polymorphisms located in the 5’ region and in the first intron of the angiotensinogen gene may contribute to the variability of plasma angiotensinogen levels.

M. L. Tuck (Veterans Administration Medical Center, Sepulveda, CA, USA) presented an up-to-date review on the role of the systemic renin-angiotensin system in obesity-related hypertension.

A. Natali (Department of Internal Medicine, University of Pisa, Italy) discussed the role of insulin resistance in obesity-related hypertension and provided data that suggesting that the sympatho-adrenergic system plays an important role in the development of obesity hypertension.

W. G. Haynes (Department of Internal Medicine, University of Iowa, Iowa City, USA), who discussed the important role of leptinergic and melanocortin influences on the sympathetic nervous system in obesity-related hypertension.

G. Seravalle (Clinica Medica, University of Milan, Italy) studied the effects of the acute blockade of corticotropin-releasing hormone (CRH) secretion induced by dexamethasone (DEX) on the sympathoexcitatory response elicited by insulin.

A. D. Strosberg (Institut Cochin de Génétique Molèculaire, Paris, France) discussed the potential role of beta-3 adrenergic receptors in the development of obesity.

S. L. H. Schiffelers (NUTRIM, Department of Human Biology, Maastricht University, Maastricht, The Netherlands) on the effects of beta 1- and beta 2-adrenoreceptors–stimulated thermogenesis and fat oxidation in lean and obese men.

S. Rössner (Huddinge University Hospital, Sweden) presented the first clinical data on a new lipase inhibitor orlistat which reduces the absorption of dietary fat by 30% and reduces weight and blood pressure.

R. Donelly (University of Nottingham, Division of Cardiovascular Medicine, Nottingham, UK) reviewed the pharmacological treatment of obesity-related hypertension.

P. G. Kopelman (St. Bartholomew’s Hospital and The Royal London School of Medicine, University of London, UK) provided an outlook of the management problems that will become apparent in the early part of the 21st century.

With this roster of leading experts, it was perhaps not surprising that we attracted over 150 attendees from over 30 countries to his ‘impromptu’ meeting.

It turns out that this was to be only the first of a total of four ISOH meetings, the last held in 2005, by which time I had not only made a name for myself in obesity (having been appointed to a Tier 1 Canada Research Chair in Cardiovascular Obesity Research and Management at McMaster University in 2002), but had also managed to build professional and personal relationships around the world that last to this day.

I also learnt important lessons that formed the very basis for eventually creating the Canadian Obesity Network, now with almost 7,000 members, by far the largest national professional obesity association in the world.

For those, who would like to read more about the symposium, the proceedings were published in Kidney and Blood Pressure Research in 2000.

For anyone who may have attended the event (or any of the subsequent ISOH meetings), I’d love to hear about your recollections of these Symposia.

AMS
Edmonton, Canada

Sharma AM, Distler A, & Hauner H (2000). International symposium on obesity and hypertension genetics and molecular mechanisms. Genetics and molecular mechanisms Kidney & blood pressure research, 23 (1), 49-72 PMID: 10567854

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Diurnal changes in hormones and metabolism are well known and how these can be influenced by timing and sequencing of external stimuli (e.g. eating, exercise, sleep, etc.) has always been of considerable interest.

A study by Sigal Sofer and colleagues from the Hebrew University of Jerusalem, Israel, published in OBESITY, suggests that eating most of your carbs at dinner may have beneficial effects on hormonal patterns, metabolism, and lead to more weight loss than eating a similarly calorie-restricted diet with carbs spread out throughout the day.

The rationale for the study as stated by the researchers is that:

“…consumption of carbohydrates mostly in the evening would modify the typical diurnal pattern of leptin secretion as observed in Muslim populations during Ramadan. The experimental diet induced a single daily insulin secretion in the evening, thus it was predicted that the diet would lead to higher relative concentrations of leptin starting 6–8 h later i.e., in the morning and throughout the day. This may lead to enhanced satiety during daylight hours and improve dietary adherence.”

In addition,

“Studies have shown that there is a negative correlation between insulin and adiponectin levels. Since the experimental diet used in this study reduces insulin secretion during the day, it was also hypothesized that adiponectin concentrations would increase throughout the day improving insulin resistance, diminishing symptoms of the metabolic syndrome and lowering inflammatory markers.”

A total of 78 male subjects (policemen) with a BMI greater than 30 were randomized to 6 months of 1,300–1,500 kcal/day diets, with either the carbs served mostly at dinner (test) or throughout the day (control).

Subjects eating their carbs in the evenings lost more weight (11.6 vs. 9.06 kg) and had lower hunger scores as well as greater improvements in fasting glucose, average daily insulin concentrations, and insulin-resistance.

There were also greater improvements in lipid profiles, CRP, and other relevant markers in the intervention group.

While leptin levels dropped in both groups (not surprising given the weight loss), the leptin decrease was less in the late-carb-eaters than in the control group, and adiponectin levels increased significantly only in the intervention group. The authors suggest that these hormonal changes may perhaps explain the improved metabolic control and lower hunger scores in this group.

However, the authors are also careful to point out that:

“Further research is required to confirm and clarify the mechanisms by which this relatively simple diet approach enhances satiety, leads to better anthropometric outcomes, and achieves improved metabolic response, compared to a more conventional dietary approach.”

They certainly have my attention.

AMS
Edmonton, Alberta

p.s. Registration for the International School on Obesity Research and Management (ISORAM 2012, Lake Louise March 25-30 is now open - click here to register).

Sofer S, Eliraz A, Kaplan S, Voet H, Fink G, Kima T, & Madar Z (2011). Greater weight loss and hormonal changes after 6 months diet with carbohydrates eaten mostly at dinner. Obesity (Silver Spring, Md.), 19 (10), 2006-14 PMID: 21475137

I am currently in Cambridge, UK, as part of the faculty of SCOPE (Specialist Certification of Obesity Professional Education), the official inter-professional educational program of the International Association for the Study of Obesity (IASO).

This year’s participants include a significant delegation from India, which is in the midst of its very own obesity epidemic.

While it is rare to see severe obesity (BMI levels over 40) in people of South Asian origin, there is now ample evidence suggesting that this population is particularly prone to the cardiometabolic complications of obesity even at a rather moderate increase in BMI.

In a study I co-authored with Sonia Anand and other colleagues from McMaster University, Hamilton, ON, published online today in PLoS one, we show that this increased risk may be attributable to adipocyte hypertrophy and increased ectopic fat deposition.

For this study, we recruited 108 healthy South Asians (defined as parents and grandparents who originated from India, Pakistan, Sri Lanka, or Bangladesh) and white Caucasians (ancestors originated from Europe) into one of three BMI strata: ≤25 kg/m2, 26–29 kg/m2, ≥30 kg/m2, matched for sex and age.

Measurements included body composition, adipocyte size, abdominal fat area (MRI studies), and hepatic adiposity (MRI-spectroscopy) were assessed and related to fasting glucose, insulin, lipids and adiponectin levels.

After adjustment for age, sex, and BMI, South Asians had more body fat, lower lean muscle mass, increased waist to hip ratio, less superficial subcutaneous abdominal adipose tissu, more deep/visceral to superficial adipose tissue ratio, and more liver fat than their Caucasian counterparts.

South Asians also had higher fasting insulin, lower HDL cholesterol, and lower adiponectin levels.

Most interestingly, fat cell size, measured as adipocyte area, was increased in South Asians compared to white Caucasians, and this difference in adipocyte size accounted for almost all of the observed differences in metabolic parameters and fat distribution.

Thus, this form of ‘ethnic’ lipodystrophy’ may well play an important role in the increased risk of South Asians even at lower BMI levels.

Although, this is a small cross-sectional study, the consistency of our findings with other reports in the literature, lead us to consider the following clinical implications:

1) Young, apparently healthy South Asians have greater metabolic impairment compared to white Caucasians who tend to develop metabolic changes at higher levels of obesity and at a more advanced age, supporting earlier screening for abdominal adiposity and elevated glucose among South Asians.

2) It is likely that the metabolic changes observed in South Asians may be prevented by avoiding chronic over nutrition, thereby preventing its consequences (including adipocyte hypertrophy, abdominal adiposity, and ectopic fat deposition).

3) It is also likely that adipocyte cell size and metabolic risk factors in South Asians could be reduced by treating obesity and/or by shifting fat deposition from ectopic sites to subcutaneous depots using pharmacologic agents (i.e. PPAR gamma agonists).

These findings obviously also apply to those of South Asian descent living in countries like Canada, where specific measurement and treatment guidelines may need to address the specific needs of this important visible minority.

AMS
Cambridge, UK

p.s. I’d like to personally thank the many participants in this trial, who volunteered their time and subjected themselves to a daunting battery of tests, including fat and muscle biopsies.

Yesterday, I posted about the presentation of Columbia University’s Rudy Leibel on how losing weight results in a hypometabolic and orexogenic response mediated largely by a fall in plasma leptin levels that, as a rule, accompany any attempt at reducing fat stores.

This post elicited a number of responses that I will try to address in this follow-up post.

Several readers wanted to know whether there is a way to readjust your ‘leptin sensitivity’ so that the brain no longer wants to restore body weight to pre-weight loss levels.

The short answer is ‘no’. Although there are several proposed strategies (special diets, refeeding days, exercise strategies, etc.) floating around in the popular literature, there is very little scientific evidence that this can actually be done. The sad fact is that anyone, who has ever lost weight, has to continue with efforts to keep it off - this includes people who have had bariatric surgery, who if they ever decide to reverse their surgery - will rapidly gain their weight back (even after years of keeping it off). This, by the way, is why bariatric surgery has to be seen as a definitive and permanent solution and why temporary devices like gastric balloons, which have to be eventually removed, are not a permanent treatment for obesity.

Another reader wanted to know, that if this was true, why some people are successful in maintaining long-term weight loss.

The answer to this is that these individuals somehow manage to continue their efforts (whatever those may be) in the long-term. The best studied group of individuals who have succeeded in the long-term are perhaps those represented by the National Weight Control Registry, who, using various strategies manage to reduce their caloric intake to about 1400 KCal (the same amount that is effectively eaten by successful post-bariatric surgery patients) combined with considerable amounts of exercise (upto 400 KCal worth every day). Such ongoing efforts are clearly beyond what most people can do without completely changing their lives. So, what the NWC participants actually demonstrate, is not so much that sustaining weight loss is possible but rather that this requires an almost ’superhuman’ effort (some would say ‘obsession’) - indeed the NWC registrants represent a rare minority of people attempting to lose weight by diet and exercise alone (the NWC registry has a few thousand registrants compared to the tens of millions who try losing weight every year).

Finally, some readers wondered about ‘leptin resistance’, a term often used to describe the fact that obese people apparently need higher circulating levels of leptin (hyperleptinaemia) to suppress their appetite and burn more calories than lean people.

In his talk, Leibel made clear that ‘resistance’ may not be the best way to describe this phenomenon.

Rather, he preferred to refer to an elevated leptin ‘threshold’, implying that there is an upward shift in the levels of leptin required to suppress the orexogenic and hypometabolic response elicited by caloric restriction.

Leibel prefers the term threshold, because even in people with a high threshold (i.e. obesity), once you have administered enough leptin to restore baseline levels and suppress the orexogenic response that follows weight loss, there is no further decrease in appetite, even at higher leptin doses. This is why simply injecting additional leptin into a person who is at their usual weight (i.e. prior to weight loss) has little to no effect on appetite, which incidentally, is exactly why leptin does not produce weight loss and would not meet thergulatory criteria for as a weight-loss drug (the rare exception being in individuals who are born with a genetic lack of leptin).

Perhaps the difference between ‘resistance’ and ‘threshold’ can best be understood by comparing leptin to insulin. In people who are resistant to insulin (e.g. patients with type 2 diabetes), you can ‘overcome’ this resistance by simply injecting increasing amounts of insulin. Even in the most insulin-resistant individual, you can eventually lower blood glucose levels by injecting more insulin - if you inject too much, these individuals will experience hypoglycemia, i.e. experience the physiological impact of too much insulin.

In contrast, the hypometabolic and orexogenic state following weight loss will respond to leptin injections only up to a dose that is just high enough to restore pre-weight-loss levels (the threshold level) - adding additional leptin will not increase metabolism or suppress appetite further.

Thus, while people with insulin resistance will respond to increasing doses of insulin to the point of hypoglycemic shock, people with an elevated leptin threshold will achieve a maximum metabolic and anorexogenic response (albeit at higher levels than people with a lower threshold) beyond which leptin has no further effect.

This may seem like a ’semantic’ distinction but from a treatment perspective (and the science behind it), this difference is substantial and explains why high doses of insulin can always be used to treat diabetes even in the most insulin-resistant individual whereas leptin only works upto the point where it restores levels to the respective (pre-weight loss) threshold.

Obviously, the key question is why some people have a higher leptin threshold or rather why this threshold (that can also be thought of as the famous ’set point’) only seems to move in one direction (namely to higher levels) and then becomes permanent (unless it is moved to even higher levels by weight gain).

As Leibel explained, the reason that this leptin threshold appears permanent, may be due to the fact that it becomes ‘hardwired’ into the brain - a process that is essentially irreversible (perhaps with the exception of patients with cancer cachexia). It is therefore perhaps not surprising that it actually takes neurosurgery (in animal experiments) to ‘reverse’ this threshold - an approach that is clearly not feasible in humans.

Several readers also asked whether leptin is available and whether it works in humans to help keep weight off - more on this topic tomorrow.

In the meantime, here is a link to a previous post on Leibels ‘Threshold Theory‘.

AMS
Edmonton, Alberta