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The Physiological Basis for Weight Regulation

Body weight regulation is influenced by multiple physiological processes so here's a list of major ones responsible for weight control.
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SPEAKER: This lecture will provide a summary of the regulation of body weight and its relevance to obesity. Weight maintenance, or weight homeostasis, has been simplistically considered a biological scenario in which energy expenditure, or energy out, matches energy in from food intake.
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Energy expenditure is comprised of three principal components– resting energy expenditure, which is the energy expenditure in resting processes such as cardiopulmonary activity; thermal effect of feeding, which is the energy required to digest, transport, and deposit nutrients; and third, non-resting energy expenditure, or that from physical activity. So in most people, even though there is high variability in what we eat day to day and how much physical activity we do, cumulative energy intake and output is matched over an extended period of time such that a set body weight is maintained.
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But we can all understand that exceeding energy intake relative to output would result in weight gain, and exceeding energy output relative to energy intake would result in weight loss. But it really isn’t as simple as all that. For most people, most of the time, the body has a weight set point that is unique to each individual depending on genetic factors. And it’s driven by biological homeostatic mechanisms. These mechanisms are complex. And the evidence shows us that weight homeostasis cannot readily be simplified to an in-out equation that covers all individuals, and without understanding the energy out processes.
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I’m sure we all know people who can eat large amounts of food with very little energy output, and yet maintain their weight– whilst for others, they expend vast amounts of energy, and yet have very little food intake, but still seem to put on weight. It is obvious that both of these individuals have a very different homeostatic set point for their weight, and that the differences are between individuals’ metabolism.
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So when we consider the 3 components of energy expenditure, resting energy expenditure is the greatest contributor to energy output, at 60%. We often think about resting energy expenditure being driven by muscle mass. But, in fact, it’s far more complex than that. This is then followed by non-resting energy expenditure coming from physical activity, which contributes much less– around 30% of energy output. And then, finally, the thermal effects of feeding, making up around 10%. So it’s really resting energy expenditure that’s the key to weight maintenance. And this is driven by biological mechanisms, which vary between individuals and at different stages of life.
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So by what biological mechanisms is weight maintained? Weight is highly regulated. And the drive to eat extends well beyond willpower. There are a growing number of molecules that have been implicated in energy homeostasis, which raises many possibilities for how regulation occurs. And we’ll only cover the major players here. But the vast number of molecules involved in weight regulation also provides numerous potential pathways for pharmacological treatments for weight management in severe obesity. But it also explains why, at present, there is no quick pharmacological fix.
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The biological process by which weight is regulated is considered in two interrelated components– central control and peripheral control, involving the gastrointestinal system and adipose tissue.
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Central control is regulated in the arcuate nucleus of the hypothalamus. And this is the primary brain region involved in appetite homeostasis. Within the arcuate nucleus, there are two interconnected groups of neurons, which have opposite effects on energy balance. Neurons which express neuropeptide Y and agouti-related peptide stimulate food intake.
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And neurons which inhibit the desire to eat are those in the arcuate nucleus, expressing alpha-melanocyte stimulating hormone. The 2 clusters of neurons within the arcuate nucleus of the hypothalamus communicate with the paraventricular nucleus and the lateral hypothalamus, where other appetite suppressing or stimulating molecules are expressed. You can also see from this picture here that, obviously, the higher function regions of the cerebral cortex that influence conscious thought can also influence these pathways. And these pathways can be influenced for both long-term and short-term regulation of weight.
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Short-term energy balance is driven by control of hunger and appetite. The peripheral control of hunger and appetite is driven by hormonal signals generated from the gastrointestinal system– including the pancreas– but also from the endocrine functions of adipose tissue. Stored white adipose tissue secretes adipokines, with the most important adipokine in the weight regulation process being leptin. As we’ve covered in an earlier module, leptin also has pro-inflammatory roles and is a contributor to the development of osteoarthritis. In the weight regulation process, it is a hormonal indicator of longer-term energy balance, as is insulin. Under normal circumstances when an individual is in weight homeostasis, or a stable weight, leptin is released proportional to adipose tissue volume.
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And its role in the hypothalamus is to inhibit the expression of NPY and AgRP so as to inhibit the hunger stimulation pathways, and stimulate the appetite suppression pathways, to promote a reduction in food intake. So you should be getting an idea now that leptin appears to be a key player in both obesity as well as osteoarthritis. And there is evidence that pathological leptin deficiency or leptin resistance in the central nervous system results in severe obesity.
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So when we think about peripheral mediators for weight regulation, leptin– secreted from the fat cells– and insulin– secreted by the pancreas– are the hormonal mediators responsible for longer-term energy balance.
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So for hunger or short-term regulation of weight, peripheral mediators driving hunger are expressed from cells in the gastrointestinal tract and the pancreas. Apart from ghrelin, which stimulates hunger, the other signals from the gastrointestinal tract promote satiation or fullness.
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These mediators travel via the bloodstream and via the vagus nerve to the hypothalamus, where they influence the balance of activity between the two opposing arcuate nucleus circuits to modulate appetite and energy expenditure.
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So in summary, you can see that regulation of weight is through appetite. And this is influenced by central and peripheral pathways. These influence both short-term and long-term weight regulation, with long-term regulation being more from leptin and insulin.
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Primarily, this homeostatic regulation was designed to protect against weight loss much more vigorously than weight gain. This is clearly helpful for survival when food is scarce, as it was for most of human evolution. However, that is clearly not the case now for most people living in developed nations.
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And we know that our drive to eat is influenced by biological mechanisms such that our drive to eat extends beyond conscious thought or willpower. But evidently, there are also non-homeostatic influences at play.
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And meeting our nutritional requirements is not our sole motivation for eating. In this society we live in, we are very rarely in a situation of energy deficit. And people certainly can have a desire to eat, irrespective of whether their energy stores are adequate. Sight, smell, and palatability of food influence desire to eat through central reward pathways.
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There is a very large social component to eating. And it is part of our social connectedness, with sharing meals and food. It’s an enjoyable experience. These external factors influence the reward pathways in the brain.
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And this is what is termed in the literature as the hedonistic influence on appetite.
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This term refers to the reward circuits in the limbic system that feed into the hypothalamus, the limbic system being a collection of structures located in the middle of the brain. Inputs into the limbic system driven by food sights, smells, and emotional factors will stimulate reward circuits within the limbic system. And these can override the homeostatic system and increase the desire to consume palatable, energy-dense foods, regardless of homeostatic status.
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But also, the hormone leptin, from adipose tissue, has been shown to influence taste and reward pathways in the limbic system. Similarly, ghrelin, the hormone secreted by the stomach to stimulate appetite, also affects the limbic system, stimulating the mesolimbic dopamine pathway and increasing the desire for sweet foods.
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So as you can see, there is a very complex interplay between homeostatic and hedonistic pathways influencing weight regulation, and that there are also biological mechanisms which exist to enhance our desire for food.
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So in summary, the key points from this presentation is that weight homeostasis is a complex process involving central and peripheral control processes. Resting energy expenditure counts for nearly 2/3 of our energy expenditure, with less– around 1/3– coming from non-resting expenditure from physical activity. And weight loss and maintenance is far more complicated than just willpower and energy balance– energy in versus energy out.
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And here are some of the references from this talk.

Watch this lecture video to learn about how body weight is regulated.

Regulation of Body Weight Is Complex

Whilst regulation, or homeostasis, of body weight is most simplistically considered as an equilibrium between “Energy In” and “Energy Out”, the energy out regulation is extremely complex.

Three components of energy expenditure. Non-Resting Energy Expenditure 30%. Resting Energy Expenditure 60%. Thermal Effects of Feeding 10%.

In adults with a stable weight, Resting Energy Expenditure is the greatest contributor to energy output, between 60 and 70%.5 This is the energy expended on resting processes such as cardio-pulmonary activity.

Non-resting energy expenditure only accounts for 20-30% of energy output, and this relates to the energy expended during physical activity or non-sedentary behaviour. Hence it is important that when we think about exercise prescription for patients as part of their weight loss management plans, we understand this is a lesser component of the homeostasis equation compared to resting energy expenditure.

Finally, the thermal effects of feeding make up the remaining ~10% of energy expenditure.6

Central and Peripheral Processes Involved in the Homeostatic Regulation of Body Weight

For adults, despite wide variability in our day-to-day eating habits and physical activity, weight is maintained in a stable or narrow range for long periods of time. This is due to the central integration of peripheral signals about fat stores, energy intake, and longer-term energy stores.

Central Control

The primary brain region involved in appetite homeostasis is the arcuate nucleus of the hypothalamus, which projects to other brain regions such as the paraventricular nucleus and the lateral hypothalamus. Two interconnected groups of neurons in the arcuate nucleus have opposite effects on energy balance with some hormones increasing appetite and stimulating food intake and others suppressing appetite and inhibiting the drive for food.

However, it is evident that our desire to eat extends beyond a motivation for energy intake balance. The limbic system, our conscious will, and reward circuits all influence these central pathways.

Peripheral Control

Peripheral control of hunger and appetite is driven by hormonal signals generated from adipose tissue (leptin), the pancreas (insulin), and the stomach (ghrelin). These hormones travel through the bloodstream and via the vagus nerve to the brainstem and onto the hypothalamus and other areas of the brain including the area postrema and nucleus of the solitary tract. There are reciprocal pathways between these regions. Short term regulation of food intake is driven mainly by hormonal signals from the gastrointestinal system as follows:

Appetite increasing hormones: Ghrelin (produced in the stomach) is the major hunger-stimulating hormone) Appetite suppressing hormones: Glucagon-like peptide (GLP-1), amylin and peptide YY produced within the gastrointestinal tract

Long-term regulation of weight and appetite is driven by peripherally released hormones including LEPTIN (secreted by adipose tissue) and INSULIN (secreted by the pancreas). Under normal circumstances when an individual is in weight homeostasis, leptin is released proportionally to the volume of adipose tissue. Leptin travels to and acts on neurons in the brain to inhibit the neurons involved in the hunger stimulation pathways. Leptin is a key player in obesity, with experimental studies showing that pathological leptin deficiency or leptin resistance in the central nervous system results in severe obesity. Insulin is secreted by the pancreas and similarly acts to suppress appetite.

Image of brain. Inside the brain = Cerebral cortex (conscious will) -> Paraventricular nucleus (Oxytocin and CRH). Arcuate nucleus (NPY, CART, AgRP, aMSH)-> Paraventricular nucleus and Lateral Hypothalamus (Orexin. MCH). Paraventricular nucleus and Lateral hypothalamus -> Brain Stem. Brain stem -> Lateral Hypothalamus. NTS/Vagus -> Brain Stem. Leaving the brain Food intake and Energy expenditure. Stomach (Ghrelin) -> Hunger Stimulation. Gut (CCK, Oxnto-modulin, GLP-1, PYY3-36), Fat (Leptin), and Pancreas (Amylin, Insulin, PP) -> Hunger Inhibition

Figure: Simplistic summary of hormone interaction and central control of weight regulation. Modified from Proietto J. 2011. Medical Journal of Australia7

Use the points discussed in this video in your approach to weight management.

 

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