Dr. Sharma's Obesity Notes

Dr. rer. medic. Iris Kunz

In 2000, one of my doctoral students, Iris Kunz examined the relationship between resting metabolic rate and obesity related hypertension in human volunteers.

Based on our longstanding interest in the sympathetic nervous system, we hypothesized that increased sympathetic the increased sympathetic activity commonly associated with hypertension in obese subjects, would result in higher resting metabolic rates.

For this study we used indirect calorimetry to determine basal substrate use and metabolic rate in 166 normotensive and hypertensive normal weight or obese subjects. It turned out that 42 of the 91 hypertensive subjects were on beta-adrenergic blockers and had significantly reduced metabolic rates - these were excluded from the subsequent analyses.

In the remaining subjects, we found an almost 10% higher metabolic rate in the hypertensive compared to the normotensive subjects. This higher rate was associated with higher levels of plasma catecholamines and leptin, as well as an increased insulin response to an oral glucose load.

In our paper published in HYPERTENSION, we discussed these findings a supporting our hypothesis that the elevated sympathetic activity seen in obese hypertensive subjects would be associated with an increased metabolic rate.

Although these findings may not have any immediate clinical implications, they do provide some insight into how neurogenic and metabolic factors may play a role in obesity hypertension. Certainly, it is always comforting when actual findings are in line with what we would have predicted based on what we know about obesity, sympathetic activity, and metabolic rate.

According to Google Scholar, this paper has been cited 46 times.

As some readers may be aware, the heart, apart from simply pumping blood through our arteries, also secretes hormones called natriuretic peptides, which play an important role in regulating blood volume. Natriuretic peptide levels tend to be markedly increased in patients with heart failure.

Now, a study by Marica Bordicchiia and colleagues, from the Sanford-Burnham Medical Research Institute, Orlando, Florida, published in the Journal of Clinical Investigation suggests that this hormone may also markedly affect the formation and function of brown fat.

As readers will recall, brown fat is an important determinant of caloric expenditure - a couple of ounces of this tissue can account for almost 20% of resting metabolic rate and therefore, not having enough of this tissue has been implicated as a risk factor for weight gain.

In their study, Bordicchia and colleagues not only show that cultured human adipocytes exposed to atrial NP (ANP) and ventricular NP (BNP) not only grew more mitochondria but also showed increased expression of uncoupling protein (UCP1) with increased uncoupled and total respiration.

Additional studies in mice showed that infusion of BNP into mice robustly increased UCP1 expression in both white and brown fat, with corresponding elevation of respiration and energy expenditure.

Together these findings suggest an unrecognized role of there heart hormones in the regulation of caloric expenditure by promoting the “browning” of white adipocytes to increase energy expenditure.

The authors point out that their discovery may point to a new explanation for the weight loss often associated with severe heart failure often referred to as ‘cardiac cachexia’.

In addition, as brown fat represents a natural ‘defence mechanism’ to obesity, it will be interesting to see how this hormonal pathway can perhaps be harnessed to prevent or treat obesity in humans.

AMS
Philadelphia, PA

Bordicchia M, Liu D, Amri EZ, Ailhaud G, Dessì-Fulgheri P, Zhang C, Takahashi N, Sarzani R, & Collins S (2012). Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. The Journal of clinical investigation PMID: 22307324

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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

Regular readers are well aware that losing weight is never a ‘cure’ for obesity - in fact, we know that any weight loss (by whatever means - perhaps with the exception of surgery) leads to hormonal changes that will facilitate weight regain. This is why conventional (diet and exercise) weight-loss strategies sooner or later tend to result in relapse or weight regain.

Just how pervasive and multi-faceted these long-term hormonal responses to weight loss are, is demonstrated by Priya Sumithran and colleagues from the University of Melbourne, in a paper published in the New England Journal of Medicine.

In order to examine whether or not changes in the circulating levels of several hormones involved in the homeostatic regulation of body weight persist over time, the researchers studied 50 overweight or obese individuals, who participated in a 10-week very-low-calorie-diet weight-loss program.

The 36 subjects, who completed the intervention lost about 14% of initial weight and were still well below initial weight (about 8%) 62 weeks after the start of the study.

This weight loss was associated with significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin, and amylin, whereas levels of ghrelin, gastric inhibitory polypeptide, and pancreatic polypeptide increased - most of these changes were still clearly evident at 62 weeks.

In addition, subjective levels of hunger increased and remained significantly elevated at 62 weeks.

Thus, the authors note that:

“One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss.”

Given these profound and persistent hormonal changes that affect hunger, appetite, and metabolism, it should come as no surprise that maintaining weight loss is so difficult. It certainly seems like the homeostatic system is happy to wait for the weight to come back - even if this takes several months or even years.

As I have noted before, the challenge in obesity treatment is never how to lose weight - it is all about how to keep it off. This is why, I am never too enthusiastic about new diets or medications that promise to help lose weight - unless these diets or medications also counteract or effectively block the counter-regulatory responses seen in this study, chances are that they will be ineffective in the long term.

Or, as the authors put it:

“..successful management of obesity will require the development of safe, effective, long-term treatments to counteract these compensatory mechanisms and reduce appetite. Given the number of alterations in appetite-regulating mechanisms that have been described so far, a combination of medications will probably be required.”

We do not really need new treatments for weight loss - we do, however, need treatments for weight-loss maintenance or for keeping patients in ‘remission’.

Unfortunately, the regulators still do not appear to have a pathway for approving drugs that will help with the latter.

AMS
Edmonton, Alberta

Hat tip to Bill Colmers for pointing me to this article.

Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, & Proietto J (2011). Long-term persistence of hormonal adaptations to weight loss. The New England journal of medicine, 365 (17), 1597-604 PMID: 22029981

Anyone, who has ever experienced even a mild drop in blood glucose levels, understands the notion of hunger - a drive so powerful, that almost any food will taste good (energy-dense foods will taste even better!).

But whether or not elevated glucose levels can also suppress appetite is less well studied.

As study by Kathleen Page and colleagues from Yale University, just published in the Journal of Clinical Investigation, examines whether obese and nonobese individuals regulate their desire to consume high-calorie foods differently in response to changes in blood glucose levels.

Using functional MRI (fMRI) combined with a stepped hyperinsulinemic euglycemic-hypoglycemic clamp, that allows changing the blood glucose levels in a controlled fashion, the authors show that even modest reductions in blood glucose levels preferentially activate limbic-striatal brain regions in response to food cues to produce a greater desire for high-calorie foods.

In contrast, high-normal blood glucose levels preferentially activated the medial prefrontal cortex, an area of the brain involved in regulating impulse control and reducing motivation for rewarding stimuli such as food and drugs.

Interestingly, however, higher circulating glucose levels predicted greater medial prefrontal cortex activation only in lean but not in obese subjects.

As the authors discuss:

“These results are consistent with reports showing that high BMI is associated with decreased prefrontal activity at rest and after meal consumption and that obese subjects have an attenuated postprandial deactivation of the hypothalamus. These altered obesity-associated neural responses to food cues may contribute to overeating behavior, especially several hours after consumption of high-carbohydrate meals, a time when glucose often declines significantly below baseline levels.”

Thus, as the authors conclude:

“These findings demonstrate that circulating glucose modulates neural stimulatory and inhibitory control over food motivation and suggest that this glucose-linked restraining influence is lost in obesity.”

They also speculate that:

“Strategies that temper postprandial reductions in glucose levels might reduce the risk of overeating, particularly in environments inundated with visual cues of high-calorie foods.”

One strategy to avoid drops in blood glucose levels is not to allow yourself to go hungry by consuming smaller but more frequent meals. The other is perhaps to chose low-glycemic index foods in order to prevent the ‘crash-and-crave’ drive that follows rapid changes in blood glucose levels.

The study, certainly provides further evidence for important ‘biological’ differences between non-obese and obese people - while the former experience ‘natural’ appetite suppression with high-normal glucose levels, the
latter do not experience such a suppression of appetite and will need to resort to conscious restraint - a far more difficult undertaking.

AMS
Edmonton, Alberta

p.s. Hat tip to Bill Graber for pointing me to this study

Page KA, Seo D, Belfort-Deaguiar R, Lacadie C, Dzuira J, Naik S, Amarnath S, Constable RT, Sherwin RS, & Sinha R (2011). Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. The Journal of clinical investigation, 121 (10), 4161-9 PMID: 21926468