Arya M. Sharma, MD

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

Yesterday, I posted about the observations that the same genes that confer athletic ability by increasing ‘fuel efficiency’ may also promote obesity when such activity ceases. This is in line with the ‘thrifty gene’ hypothesis, that obesity is the ‘natural’ response to genes that conferred survival advantages in our ancestors in the face of famines and increased demands on physical activity.

Interestingly, a study by Abdoulaye Diane and colleagues from the University of Alberta, just published in OBESITY, demonstrates that genetically obesity-prone animals, do in fact have a considerable survival advantage over lean-prone animals, an advantage that is further enhanced, when such animals have previously experienced caloric restriction.

The researchers took advantage of the fact that limiting access to food in mice (by restricting feeding hours) leads to an incremental increase in ‘voluntary’ wheel running associated with reduced food consumption (activity-induced anorexia) and even more running till the animals ultimately exhaust themselves and die.

In their experiments, while food restriction resulted in increased wheel running and reduced food intake in both obesity-prone and lean-prone juvenile mice, the former survived almost twice as long and lost far less of their body weight (percent and absolute values) than the lean-prone mice, which rapidly succumbed to the challenge.

Furthermore, even obesity-prone rats, who were kept lean by restricting their food to the levels of the lean-prone rats (by ‘pair-feeding’), lived longer, suggesting that this was not an advantage conferred simply by greater ‘caloric reserves’.

Interestingly, obesity-prone juvenile mice, who had previously undergone food restriction and regained their weight prior to the challenge, did even better.

Thus, not only was there a clear survival advantage in the genetically obese-prone mice but previous food restriction appeared to confer even more ‘resistance’ to the challenge.

It appear that not only do ‘obesity-prone’ genes allow animals to better cope with the dual challenge of starvation and increased physical activity, but that this ‘metabolic’ prowess can be further enhanced by prior experience with food restriction (weight loss).

Translated to humans, this later finding would suggest that ‘dieting’ makes you even more fuel efficient (which may well explain why dieting increases the risk of subsequent weight gain).

Or as the authors discuss:

“Our results show that juvenile obese-prone rats gain a survival advantage over lean-prone under famine-like conditions, and this advantage is further enhanced by physiological and behavioral changes induced by prior food restriction. In the wild, this survival advantage in young animals, that are the future breeders, would confer increased reproductive success. At a basic level, these results support the “thrifty gene” hypothesis of obesity.”

The authors further conclude:

“Thus, caloric restriction at early ages may predispose obese-prone individuals to become more metabolically efficient. An inducible increase in metabolic efficiency may help to explain the increased obesity in low- and middle-income countries where childhood under-nutrition exists in the context of rapid economic development and rural/urban migration. Thus, the obese-prone phenotype, that is highly deleterious in a food-rich environment, confers a real survival benefit in an unstable and scarce food environment, that is enhanced by prior caloric restriction.”

In summary, if these findings are indeed transferable to humans, they would have several important implications:

1) Genetically obese-prone individuals are better equipped to survive times of scarcity and/or increase physical demand.

2) This ’survival’ advantage can be further enhanced by previous exposure to caloric restriction (weight loss).

While these findings may also explain the ’survival paradox’ of obesity, where obese humans with chronic illnesses tend to live longer than skinny people with those illnesses, they also suggest an explanation for why dieting can make you fat.

I certainly do not envy the folks, who have to translate these findings into coherent ‘public health’ recommendations:

a) having genes that promote obesity is actually a survival benefit (if you should happen to encounter a famine)

b) if you are lucky enough to have these obesity genes, you can further increase your survival benefit (to famines) by (periodically?) losing weight

c) however, if you do (periodically?) lose weight, you may also end up getting even more obese - which, although a survival benefit during the next famine, will increase your risk for obesity-related health problems (in case the famine does not come).

I guess you can’t have it all.

AMS
Calgary, Alberta

Diane A, Pierce WD, Heth CD, Russell JC, Richard D, & Proctor SD (2011). Feeding History and Obese-Prone Genotype Increase Survival of Rats Exposed to a Challenge of Food Restriction and Wheel Running. Obesity (Silver Spring, Md.) PMID: 22016097

Today’s post is another excerpt from “Best Weight: A Practical Guide to Office-Based Weight Management“, recently published by the Canadian Obesity Network.

This guide is meant for health professionals dealing with obese clients and is NOT a self-management tool or weight-loss program. However, I assume that even general readers may find some of this material of interest.

METABOLISM

People often talk about their extra weight as a consequence of having a “slow metabolism.” In this context, metabolism refers to total daily energy expenditure and is made up of three components: basal metabolic rate (BMR), which is the energy spent on basal metabolism, energy spent on physical activity, and increases in resting energy expenditure in response to different stimuli such as thermogenesis or the thermic effect of food.

BMR is, for most people, the largest component of energy expenditure. It typically accounts for between 60% and 75% of total daily energy expenditure. BMR can be measured through indirect analysis of the amount of heat produced by an individual, using the amount of oxygen consumed and the Weir equations. This means of analysis is called indirect calorimetry and is the current gold standard in office-based BMR measurement. Ideally, it should be measured under standardized conditions, with the patient awake, lying in the supine position, in a resting state in a comfortable warm environment, in the morning, and 10-12 hours after the last meal. In many weight management practices, strict adherence to these conditions is often overlooked. Testing involves connecting the patient to an indirect calorimeter, which measures how much oxygen is inspired and expired during the test. Most tests take 20 minutes to complete.

By far the most important determinant of BMR is body size, in particular fat-free (lean) body mass. Even then, BMR can vary by up to 10% in individuals of the same age, gender, body size, and fat-free mass, suggesting that genetic or other factors are also involved.

Patients often overlook the fact that as they lose weight, they lose not only fat but also fat-free mass, as their muscles adapt to the lighter workload after carrying around extra weight. With enough weight loss, BMR tends to decrease. In addition, hormonal and metabolic responses to weight loss will further reduce energy requirements. Progressive weight loss means people will need fewer and fewer calories because their total daily energy expenditure has decreased.

© Copyright 2010 by Dr. Arya M. Sharma and Dr. Yoni Freedhoff. All rights reserved.

The opinions in this book are those of the authors and do not represent those of the Canadian Obesity Network.

Members of the Canadian Obesity Network can download Best Weight for free.

Best Weight is also available at Amazon and Barnes & Nobles (part of the proceeds from all sales go to support the Canadian Obesity Network)

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