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Physiological Adaptations to Weight Loss (Including Rapid and Slow Weight Loss)

Learn about the physiological response to weight loss, rapid and slow weight loss
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SPEAKER: This is a short overview about the physiological adaptations that occur in response to intentional weight loss.
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It is well known that achieving and maintaining weight loss is extremely difficult. And what we’re going to cover here in this presentation are the biological reasons why.
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As we’ve touched on, dietary-induded weight loss of 10% or more results in physiological changes to an individual’s energy out efficiency. Specifically, 10% of weight loss leads to a 15% reduction in resting energy expenditure beyond that which can be accounted for due to changes in body mass and composition. This disproportionate decline in total energy expenditure has been shown to persist in patients for over a year. What this means is that following dietary weight loss, someone’s resting energy expenditure, or their metabolic rate, is lower than it was before they started the dietary intervention.
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There is more variable data about what happens to non-resting energy expenditure with weight loss. And this is what you achieve by being physically active. It’s thought that following weight loss from a diet, no-resting energy expenditure also declines. Although, the magnitude of these changes reported in the literature are variable. But it is thought that this could be due to increased efficiency of skeletal muscle, especially at low workloads.
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So what we’ve routinely see is that people can lose substantial amounts of weight during a weight loss treatment. In this particular study, they lost around 15% of body weight. But then for the majority, there is a significant weight regain over the subsequent two to three year period after a diet. Why is this happening? It’s because the body is defending weight, to try and maintain a set point of weight. And this set point of weight is a certain level, and this level is strongly influenced by our hormonal and genetic profile. What is happening in our bodies to cause this change in energy expenditure efficiency contributing to weight regain back towards this body’s weight set point?
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The literature suggests the following physiological pathways for this defence of body weight. Changes to substrate metabolism. Changes to the autonomic nervous system. Changes to the hypothalamic pathways and the central control of appetite. Changes to appetite regulating adipocyte and gastrointestinal hormones– that is the peripheral control. And drives to subjective appetite.
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So let’s firstly look at substrate metabolism. Studies in humans and rodents show that, after dietary induced weight loss, the body moves towards a preference for using carbohydrates for energy, sparing fats for fatty deposits. This excessive preferential use of carbohydrates has been shown to reduce glycogen stores, which stimulates hunger to restore these stores. So after significant weight loss in people who are obese, the way the body uses fuel changes.
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We’ve already touched on how the hypothalamus is the primary central regulatory centre of hunger and food intake. Under normal conditions, the hypothalamus also communicates with the thyroid and, in particular, produces thyroid stimulating hormone, resulting in production of thyroxine hormones by the thyroid. The thyroid plays an important role in energy expenditure, specifically resting energy expenditure. Dieting or reducing energy intake has been shown to be associated with suppression of this communication pathway between the hypothalamus and the thyroid. However, there is variable data about whether this returns to normal during the weight maintenance phase. So we cannot be certain whether this is a contributor to weight regain.
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What about the peripheral hormonal regulators of hunger and weight regulation that are produced by the gastrointestinal system and adipose tissue? You will remember that the two major players were leptin, produced by adipocytes, or fat cells, and ghrelin, produced by the stomach. These two peripheral hormones were investigated in a landmark study in the New England Journal of Medicine by Dr. Priya Sumithran and Professor Joseph Proietto’s team.
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In individuals who have a stable weight, leptin is secreted in proportion to fat mass and acts on the pathways in the hypothalamus to suppress appetite.
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Landmark studies, such as Sumithran’s in the New England Journal of Medicine, have shown that levels of leptin are greatly reduced in individuals who are dieting, during the weight loss phase but also during weight maintenance.
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What was found in this study was that following a 10-week, very low calorie, ketogenic diet, leptin levels dropped by 70%. And these leptin levels remain 32% lower at 62 weeks, or a year after the dietary intervention. This means that people who are overweight, or obese who lose weight, have less physiological suppression of appetite because that is lepton’s normal job. So the body is trying to return to its predetermined weight or its obesity weight. And what is interesting is that at 62 weeks, these changes in hormonal levels, although trending back towards baseline or pre-dieting levels, were still well below baseline. This is important information to know because it provides evidence for a hormonal driver for weight gain– that is leptin.
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And it shows why weight maintenance is so difficult for people who are overweight or obese who engage in dietary interventions. The other key peripheral mediator from the stomach in appetite and weight homeostasis is ghrelin. And this was also investigated in this study. Opposite to leptin, ghrelin acts in the hypothalamus to stimulate appetite and drive food intake. And so you could probably predict what was found in this same study for ghrelin. It was that levels of this appetite-stimulating hormone were elevated in individuals who had been dieting, both during the weight loss phase as well as the weight maintenance phase.
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So you can see that we have all of these hormonal adaptations to weight loss in people who are overweight or obese that are working against them maintaining that weight loss. So the person has to eat less than they were before the diet in order to maintain weight loss.
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All of this is made even more challenging, taken together with the changes that occur in subjective appetite after dietary-induced weight loss in adults who have obesity. And what we have is data showing that there are increases in hunger and a desire to eat, which are driven, in part, by elevated ghrelin and reduced leptin levels. There’s also a preference for high-calorie food with high fat and high sugar. And this is, again, because of changes to the lymbic pathway. So the evidence is telling us that there is a physiological drive in people who are overweight, or obese by body mass index, who are successfully losing weight, to want to make them return to a predetermined weight set point.
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And there are further studies, particularly in people with severe obesity, where drastic weight loss is achieved, that provide evidence that metabolic rate and efficiency drops rapidly after dieting this group and stays low following a dietary intervention. This means that energy intake required to maintain weight is actually lower than before a weight loss intervention.
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Another widely cited study evaluated the changes in metabolic rate, known as metabolic adaptation, following weight loss. This study measured participants at the end of a 30-week, biggest loser competition in the UK, and then again six years later. You can see that participants lost an average 58 kilogrammes at the end of the biggest loser. Then they regained an average of 41 kilogrammes over the following six years, so that the average weight after six years was still 20 kilogrammes below baseline. And similarly, you can see that fat mass reduced and then increased somewhat over those six years. The authors really wanted to look at what drove this from a metabolic perspective.
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And they looked most closely at resting energy expenditure, or resting metabolic rate, as this is obviously the biggest contributor to energy expenditure. And they evaluated this at baseline at the end of the 30-week biggest loser competition and then again six years later. And what you can see here on this graph, with resting energy expenditure plotted on the y-axis, is that there was a 24% drop in resting energy expenditure after the biggest loser competition. And this is an amount that would be deemed clinically relevant. Further to that, at six years, it was even lower with a drop of 27% in total.
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And this drop is beyond what could be expected with loss of lean muscle mass, as some participants did lose muscle mass throughout the biggest loser process. This was a small sample, as it only included the 16 participants who entered the show. And there was variability in those who regained weight and those who were closer to maintaining weight loss. But this is a very large reduction in metabolic rate that was progressively worse six years after large amounts of weight loss. There was, however, a positive finding that came out of the study, as the authors also investigated the correlation of the reduction in metabolic rate with weight regain.
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And they found no correlation in this small sample. This could be due to the small sample, which means that the study was not sufficiently powered to see a correlation. But it could also mean that some people were able to counteract this reduction in metabolic rate by maintaining a restricted diet, thus reducing their energy intake to match the reduction in metabolic rate.
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To summarise, the physiological response to weight loss is such that a set point weight is defended in people who are overweight or obese. This makes weight loss and weight loss maintenance extremely challenging, to the point where the energy intake and energy output equation is altered after weight is lost. And so now, individuals have to consume even fewer calories than they could before the weight loss in order to maintain their new weight and not regain weight. The evidence shows us that people who are obese who lose weight have changes in substrate metabolism with a preference for carbohydrate metabolism, sparing fat for storage. They also have changes in hormone levels that regulate appetite centrally with changes in hunger and desire for tastes.
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And they have reductions in resting energy expenditure, or metabolic rate. And these changes persist for long periods of time, irrespective of whether an individual regains weight or not. So from all of this we must acknowledge that weight management is complex, and it highlights that weight is not solely under a person’s conscious control. And so we should never make judgments on someone’s lifestyle choices based on their weight. It also explains why some people will require extensive, multidisciplinary interventions to lose weight, including the need for pharmacological treatment.
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As has been was shown from long term data from one of the leading obesity clinics in Australia, they found that 1/3 of patients who undertake a ketogenic, very low calorie diet, and are supported through the clinic, do maintain significant rates of weight loss that is greater than 10% of their body weight at three years. But they also found that there is much more chance of them not regaining weight if they are prescribed appetite-suppressing medication.
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But a question that many people have is that given that most of the data are from studies where participants have rapid weight loss by engaging in a very low calorie diet, is there any difference with rapid versus gradual weight loss? Rapid weight loss obviously requires a much more intensive dietary intervention, whereas gradual weight loss can be achieved with less intensive dietary change. But what effect does the speed of weight loss have on weight regain and those physiological drivers of weight regain?
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The answer really is no. Results are shown here from a landmark study by Purcell and colleagues in 2014. In this study, they compared two groups. One group had rapid weight loss by utilising a ketogenic, very low calorie diet, including meal replacements. And the other group had more gradual weight loss through a less intensive diet. Both groups achieved around the same target of 15% body weight loss during the weight loss phase. But this phase was obviously shorter for the rapid group who lost weight quicker than the gradual weight loss group. Then over the following three years after they hit the 15% weight loss target, participants in both groups were followed and monitored for weight regain.
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You can see, as with most weight loss studies, there is a trend for people to regain some of the weight over time. But as you can see, the gradual weight loss group actually regained weight more rapidly, initially, and then to the same extent over a three year period as those in the rapid weight loss group. So there was no difference in weight regain between the two groups. And further analysis showed that the rapid weight loss group were more likely to be adherent to the programme and more likely to lose weight.
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So the key points for this presentation are that regaining weight after weight loss is common, but rate of loss doesn’t influence rate of regain. The body has a set point of weight, the level of which varies between individuals. And this weight is defended by the body when weight is lost. There are several physiological pathways for this defensive weight, which lower resting energy expenditure. Individuals will need to consume less calories than before the weight loss in order to maintain the new weight. And it highlights the complexity and difficulty in weight management for people who are overweight or obese.
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And here are the references that we used in this presentation.

Watch this lecture to learn about how the body responds to weight loss by defending body weight – and how this influences weight regain.

 Weight is Defended

The evidence shows us that the majority of people who are overweight or obese and lose 5-15% of their body weight through dieting and/or exercise, will regain weight to within 5% of their baseline weight within 3-5 years.8,9 This weight regain is thought to be driven by the long-term persistence of hormonal adaptations to weight loss, which lower resting metabolic rate or energy expenditure and drive the physiological pathways for weight regain.

Researchers have reported a 15% reduction in resting energy expenditure in participants who lost 10% of their body weight.5 To put this in simple terms, a person with a stable weight who was obese, and successfully lost weight through dieting, would then have to reduce their energy intake by approximately 15% following a diet in comparison to what they were eating before dieting to maintain their new energy in/out equilibrium and maintain a stable weight.

The literature suggests the following physiological and hormonal pathways for the defence of weight:

  1. Substrate metabolism (what is preferentially broken down for energy): After diet-induced weight loss, the body moves towards a preference for carbohydrates for energy, such that fat is stored for fatty deposits.
  2. Hypothalamic pathways: Dieting has been shown to suppress the pathways from the hypothalamus that activate the thyroid, reducing resting energy expenditure
  3. Appetite regulating peripheral hormones: Levels of Leptin, the hunger inhibitor, greatly reduce following dietary restriction both during weight loss and maintenance. Sumithran et al., 2011 showed a 70% reduction in leptin levels following a 10-week dietary intervention that was still 32 % lower than at baseline a year later. In contrast, Ghrelin levels were elevated during weight loss and after the active intervention, increasing hunger.
  4. Subjective appetite: Increased desire to eat and preference for high calorie foods persist well beyond the weight loss period and at levels beyond those pre-diet.

Read more around the hormonal defence of weight in this key research paper: Sumithran, Priya, et al. “Long-term persistence of hormonal adaptations to weight loss.” New England Journal of Medicine 365.17 2011: 1597-1604.

There is no difference for weight regain depending on whether weight is lost rapidly through very low calorie dietary interventions or more slowly
Despite the common belief that rapid weight loss results in more rapid weight regain than gradual weight loss, evidence suggests there is no difference in the rate of weight regain, and in fact, some of the advantages of rapid weight loss (as associated with a very low calorie ketogenic diet) include people being more likely to lose weight, and more likely to be adherent to dietary interventions given the motivating element of seeing results8

Potential Causes of Weight Gain

Obesity can be conceptualized as the physical manifestation of chronic positive energy balance.10 However as discussed in this module, the simple equation of ‘energy in versus energy out’ does not account for all the potential factors influencing energy balance. The following table summarises potential causes and contributors to weight gain.10 These are relevant as they can be used in the assessment and management of obesity.

Lowered Metabolic Rate: Older age, female sex, genetics, hormones, menopausal status, previous weight loss, medications, sarcopenia. Increased Energy Intake: Sociocultural factors, knowledge deficit, saboteurs, mindless eating, physical hunger, emotional eating, psychiatric disorder, sleep deprivation. Reduced Physical Activity: Sociocultural factors, physical limitations, musculoskeletal pain, cardiorespiratory conditions, beliefs about physical activity and injury, chronic fatigue, emotional barriers, psychological barriers.

Read: This review article by Sharma and Padwal is a good overview of the role of these factors in the development of obesity. You can find the article here

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EduWeight: Weight Management for Adult Patients with Chronic Disease

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