An electronic literature search was performed using the PubMed database for relevant articles published between 01 January 2008 and 30 April 2014. Given the broad nature of this review, a structured, rather than systematic, search strategy was conducted to identify relevant articles. An initial search, restricted to English-language articles and using the following key search terms: [obesity/obese/overweight] 'and' [weight] 'and' [gain/regain*] 'and' [loss/reduc*/decreas*] identified a large number [4314] of potential articles. Therefore, additional searches were then conducted to identify articles that focused on specific aspects related to this review, using the key search terms in conjunction with the following additional topics and terms: ‘physiologic*/biologic*’; ‘adapt/adaptive/adaptation/homoeostasis/homoeostatic/maintain/maintaining/maintenance’; ‘metabolic/metabolism’; ‘energy/energetic’; ‘central/peripheral’; ‘hormone/hormonal’; ‘ghrelin’; ‘leptin’; ‘insulin’; ‘pancreatic polypeptide/PP’; ‘peptide YY/PYY’; ‘cholecystokinin/CCK’; ‘amylin’; ‘glucagon-like peptide-1/GLP-1’; ‘psycholog*/neuropsycholog*’; ‘food intake’; ‘appetite’; ‘exercise/physical activity’; ‘genetic’; and ‘hedonic’. Following searches, titles and abstracts of articles were scanned to determine their relevance to the scope of this review. Articles were included if they were deemed to provide relevant information related to the scope of physiological adaptations to weight loss and factors that favour weight regain. References from bibliographies of selected articles, including reviews, original research articles and other articles of interest were scanned for additional relevant supporting articles, and data quality was determined by publication in peer-reviewed literature. Selection of articles was also based on the author’s own judgement, clinical experience, perspective and knowledge of the literature, as well as additional searches that were performed in order to address journal peer-reviewers’ comments. Articles that were not deemed pertinent to the topics covered in the review, as well as single case studies, short commentaries, letters and interviews were excluded. Overall, a total of 106 articles were included in the review.
Processes involved in the regulation of body weight
Under steady-state conditions energy intake [food] is metabolised and used to fuel basal metabolism, thermogenesis and our energy expenditure [physical activity].13 Any excess is stored as fat in adipose cells for later use. There is a genetic contribution to the determination of an individual’s weight with early-life events and parental guidance also playing a part,13, 14, 15 but ultimately steady-state body weight is influenced by a number of different factors. These factors fall into three distinct but interrelated categories: homoeostatic, environmental and behavioural processes [Figure 1].11
Figure 1
Factors affecting energy balance and thus steady-state weight. There are three main groups of factors—homoeostatic, environmental and behavioural processes—that interact and influence steady-state body weight. Alterations in any of these factors will result in changes to this steady-state and could result in obesity. AgRP, agout-related peptide; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; CART, cocaine- and amphetamine-regulated transcript; CCK, cholecystokinin; PYY, peptide YY; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; REE, resting energy expenditure; NREE, non-resting energy expenditure. ‘Central’ and ‘peripheral’ refer to the site where the molecules are produced, rather than where they necessarily act. In gthe brain, insulin acts as an anorexigenic hormone.13, 104, 105 However, in the periphery, insulin lowers blood sugar, which potently stimulates food intake.106
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Homoeostatic processes
Body weight is regulated by a complex neuro-hormonal system,11, 16 which reflects the fundamental biological importance of energy balance and nutrient supply.13 A full overview of this biological system is beyond the scope of this article and has been reviewed in detail elsewhere.13 In essence, signals involved in the homoeostatic regulation of food intake, energy balance and body weight are integrated centrally in the arcuate nucleus of the hypothalamus,17 the caudal brainstem and parts of the cortex and limbic system.13 A number of neuropeptides and hormones involved in appetite regulation function centrally in the hypothalamus; some [for example, neuropeptide Y [NPY] and agouti-related peptide [AgRP]] are orexigenic [stimulate hunger], while others [for example, pro-opiomelanocortin [POMC] and cocaine- and amphetamine-regulated transcript] are anorexigenic [suppress hunger].13, 18 The hypothalamus also processes peripheral signals that convey information about short-term food intake [that is, nutrient availability] or long-term energy balance [that is, energy stores] to achieve energy homoeostasis.11, 19 A feedback loop is created between the brain and periphery [gastrointestinal tract, pancreas, liver, muscle and adipose tissue].11, 13 Short-term signals include the orexigenic hormones ghrelin and gastric inhibitory polypeptide; the anorexigenic hormones glucagon-like peptide-1 [GLP-1], peptide YY [PYY] and cholecystokinin [CCK] from the gastrointestinal tract; the anorexigenic hormones pancreatic polypeptide [PP], amylin and insulin from the pancreas; and the anorexigenic hormone leptin from adipocytes.13, 17, 19 Insulin, however, is unique, since it reduces food intake centrally, but causes weight gain when used peripherally to treat diabetes. The hypothalamus also integrates signals from ‘hedonic’ reward pathways in the cortico-limbic system, associated with the palatability [for example, sight, smell and taste] of food.13 Such hedonic reward pathways can override the homoeostatic system and increase desire to consume energy-rich food, despite physiologic satiation and replete energy stores.13, 20 Several neurotransmitter systems in the brain, including the dopaminergic, opioidergic and cannabinoid mechanisms, have a major role in reward pathways and mediating the pleasure drive for eating.20, 21, 22
It has been suggested that, rather than something being ‘wrong’ with homoeostatic control of food intake, the system is insufficiently powered to cope with radical environmental changes and, thus, overwhelmed to the point where activation of the hedonic pathways becomes a major driving force for overconsumption.23 Recently, evidence has emerged proposing an additional mechanism by which homoeostatic control of food intake can be overridden. Dietary intake of saturated fatty acids induces inflammation in the hypothalamus, a process mediated by glial cells, which may lead to changes in neuronal function and result in disturbances to leptin responsiveness and food intake.24, 25, 26, 27 Glial cells may, therefore, have an important role in the regulation of body weight, with chronic activation of glial cells linked with the perpetuation of obesity and the onset of related complications.25, 26, 28, 29
Environmental
The environment in which we live has an important role in influencing energy homoeostasis. Current levels of obesity are attributable, at least in part, to an ‘obesogenic’ environment that impacts cortico-limbic brain areas concerned with learning and memory, reward, mood and emotion.30 Contributing factors to this environment include intense marketing of energy-dense foods, increased availability of these foods and increased portion sizes, which all present people with the opportunity to over-consume large portions of sugary and high-fat foods.31, 32 Moreover, a high-stress society stimulates compensatory food intake.15 This increase in food intake is coupled with decreases in physical activity, for example, because of sedentary jobs15 and a decline in the promotion of physical education in schools.31, 32 Ultimately, an ‘obesogenic’ environment makes it more challenging for individuals to maintain a healthy body mass index [BMI] through diet restriction or maintaining healthy levels of physical activity.
A number of other factors have also been postulated by McAllister et al.32 to contribute to obesity, including infection, epigenetics, increasing maternal age, greater fecundity among people with higher adiposity, assortative mating, sleep debt, endocrine disruptors, pharmaceutical iatrogenesis, reduction in variability of ambient temperatures, through to intrauterine and intergenerational effects [Table 1]. Our understanding of the contribution of these factors to obesity is variable, with much evidence based on epidemiological and pre-clinical data,32 but there is increasing interest in the literature and a number of factors are worthy of further consideration. As McAllister et al. note, with an increasing prevalence over time of many of these proposed factors [for example, sleep debt and epigenetics] combined with an increasing prevalence of obesity, further research into the impact of these factors in modulating obesity is warranted [Table 1].
Table 1 Environmental factors potentially influencing body weight
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Behavioural
How we behave also influences our energy homoeostasis. It is apparent that simply knowing that a healthy diet and exercise will result in weight loss is not sufficient to reach and maintain a healthy lifestyle and reduce excess body weight.15 Behaviour patterns are a fundamental contributor to the aetiology of obesity and, therefore, behavioural therapy is often a key part of the management of obese individuals.33 A proportion of obese individuals do successfully maintain weight loss and this is associated with specific changes in behaviour, particularly with regard to diet and exercise.33 In a recent study, 110 obese women who completed a 6-month lifestyle intervention were assessed in terms of weight loss maintenance over a 3.5-year period.34 Those candidates who maintained weight loss [⩾5% reduction in body weight] exhibited more frequent self-monitoring of food and calorie intake, selected lower calorie foods, planned meals in advance and weighed regularly.34 Recent findings from the National Weight Control Registry—comprising over 2800 individuals who have maintained a weight loss of ⩾13.6 kg for⩾1 year—demonstrate that sustained behaviour change can lead to long-term maintenance of weight loss.35
Personal motivation for change can have a fundamental role in modifying unhealthy habits and lifestyle.15 The importance of promoting self-efficacy in increasing physical activity in obese individuals has recently been highlighted; for example, improvements in self-efficacy following interventions have been shown to correlate with improved physical activity behaviour.36 Self-efficacy is the ‘belief that an individual has the ability to successfully engage in a specific behaviour such as exercise’.36 In a meta-analysis of 61 studies, four behaviour change techniques [‘action planning’, ‘time management’, ‘prompt self-monitoring of behavioural outcome’ and ‘plan social support/social change’] were significantly associated with positive changes in self-efficacy. ‘Prompt self-monitoring of behavioural outcome’ and ‘plan social support/social change’ and an additional 19 behaviour change techniques were also associated with positive changes in physical activity.36 The concept of discrepancy, the contradiction between how a person currently sees him/herself and how he/she would like to be, in order to correspond to his/her ideal self-image, value system and expectations, as well as the concept of self-regulation, are also recognised as important components in realising behaviour change.15
Physiological adaptations to weight loss and factors favouring weight regain
Evidence continues to accumulate that the compensatory changes in biological pathways involved in appetite regulation, energy utilisation and storage encourage weight regain following weight loss. These changes affect our complex neuro-hormonal system that regulates energy homoeostasis, including perturbations in the levels of circulating appetite-related hormones and energy homoeostasis, as well as alterations in nutrient metabolism and subjective appetite [Figure 2].
Figure 2
Physiological factors driving weight regain after weight loss. Changes in specific parameters that drive weight regain are indicated in red. AgRP, agout-related peptide; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; CART, cocaine- and amphetamine-regulated transcript; CCK, cholecystokinin; PYY, peptide YY; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; REE, resting energy expenditure; NREE, non-resting energy expenditure. ‘Central’ and ‘peripheral’ refer to the site where the molecules are produced, rather than where they necessarily act. In gthe brain, insulin acts as an anorexigenic hormone.13, 104, 105 However, in the periphery, insulin lowers blood sugar, which potently stimulates food intake.106
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Levels of circulating hormones
Appetite-related hormones have a key role in weight regain after weight loss.37 With the exception of increases in PP,19, 38 changes in hormones following weight loss tend to favour weight regain by increasing hunger and promoting energy storage.19, 38 For example, following diet-induced weight loss, there are increases in levels of ghrelin,39 and gastric inhibitory polypeptide19 with decreases in levels of leptin,19, 40 PYY,41 CCK,42 amylin,19, 43 insulin19, 38, 43 and GLP-1.44, 45 Findings from a study of 50 overweight or obese individuals demonstrated that such hormonal alterations in response to weight loss, following a 10-week very-low-energy diet, can persist long term [~1 year].19 One year after the initial weight loss, significant differences [P