Physiology of Body Weight, Weight Gain and Adipose Tissue Background 

 

Contributors

Importance of Topic to Practice
For years, individuals with larger bodies have been told by medical providers, government agencies and society in general that having a higher body weight is harmful to one’s health and the health care system (1-3). Individuals with a higher body weight are often subjected to weight bias, stigma and discrimination (1) and are often told to lose weight in efforts to improve their health. Until recently, much of the global health care education and public health messaging has been rooted in individual responsibility for weight control, emphasized by an “eat less/move more” mentality with the goal of achieving a ‘healthy’ weight. This has been extrapolated from previous human physiology evidence that states energy balance is achieved by having equal energy intake to energy expenditure based on the principal law of thermodynamics (4,5). Weight gain is therefore a result of excessive energy intake or inadequate energy expenditure, while weight loss is achieved by reducing energy intake and/or increasing energy expenditure (6,7). These basic thermodynamic principles have caused a culture of dieting, caloric restriction and weight-loss-centric thinking, which has contributed to the growing evidence on weight stigma (See Additional Content: Weight Stigma Background). Advances in the science of, and the social impact of, weight stigma as well as advances in biology, physiology and metabolic studies have changed the understanding of the factors that affect weight regulation and eating behaviours. These include the metabolic function of adipose tissue, genetic factors affecting weight, metabolic adaptation in response to weight change and differences between non- and pathophysiological body weights. Outdated evidence and a lack of understanding about the complex intersections affecting body weights may result in health care professionals and the public at large feeling confused. This background paper provides an updated understanding of the physiological factors contributing to body weight regulation and appetite changes in response to weight change, based on the best available evidence at the time of writing. Applying this updated evidence to clinical practice may support a better client-provider relationship and potentially decrease weight-related bias and stigma in the nutrition field.  
 
Topic Overview
Most public health and clinical health messaging has used epidemiological studies that define healthy weights using BMI. Studies have continually found a U-shape association with lower and higher BMI categories with morbidity (health) and mortality (death) risks (8,9). Over the past three decades, rates of higher weights have increased and continue to be reported as a health and economic crisis (3,8,10,11). Historically, having a BMI >30 kg/m2 was defined as ‘obesity’ and was associated with an increased risk of diabetes, cardiovascular disease and some cancers (12-17), resulting in decades of research, public health campaigns and societal messaging targeting weight loss efforts to achieve ‘healthy weights’ (BMI 18.5-24.9 kg/m2) (18,19). Despite the efforts to reduce the incidence of obesity (using BMI definitions) or treating obesity via weight loss, weight gain has continued to rise (20) and has further perpetuated weight bias, stigma and discrimination among individuals with higher body weight. See Additional Content: Weight Stigma Background.
 
Recent progress in animal and human studies exploring the genetic, physiological and metabolic variances across weight spectrums has changed the understanding of body weight and health, suggesting that having a higher body weight may not be associated with poor health at the individual level (21-23). In 2020, the Canadian Adult Obesity Clinical Practice Guidelines recommended against using BMI to define obesity at the individual level (24,25) and instead recommended an updated definition (“defined as abnormal or excess adipose tissue impairing health”) reflecting the evidence in genetics, metabolic/physiological, environmental and social determinants of health impacting body weight (specifically adipose tissue) (24). The shift in definition has been echoed in literature (26-29) and accepted by a number of organizations (30-37) and countries (38-43) but remains a topic of controversy (44-47). Redefining obesity beyond BMI classifications serves to support cellular and organ-level evidence that adipose tissue dysfunction can occur across all weight spectrums, similar to other organ-specific diseases that occur across weight spectrums such as diabetes, chronic kidney disease or atherosclerosis (48). This narrative supports body diversity by acknowledging that body weight and BMI are not indicators of health or disease processes (27,49,50) and that focusing on health-related behaviour changes is universal regardless of one’s body weight, size or BMI (51,52). 

Relevant Basic Information
Review of Adipose Tissue
Evidence at the genetic and cellular level of adipose tissue has contributed to further understanding that adipose tissue (adipocytes) is essential for metabolic and endocrine-related mechanisms in the body rather than purely an innate organ that stores excess energy (53). Furthermore, these endocrine functions stimulate hormones, enzymes and other endocrine-communication modulators that affect human survival and metabolism (54).
 
Adipose tissue, specifically adipocytes, are heterogenous in nature both metabolically and genetically (54,55). Adipocytes can increase in size, known as adipocyte hypertrophy, and can increase in the number of adipose cells, known as adipocyte hyperplasia (54). The human body has various adipose deposit sites, primarily known as subcutaneous adipose tissue (typically distributed in extremities – hips, legs, arms), and visceral adipose tissue (centrally distributed around organs) (54). The location and action of adipose tissue is the most important, as increased adipose tissue (by hypertrophy or hyperplasia) does not necessarily indicate a disease process; however, like any tissue, it can become dysfunctional by secreting a variety of biologically active molecules called adipokines, that can modulate inflammation (54,55). When adipocytes progress to release these inflammatory molecules (adipokines), this can lead to ectopic fat deposits in pancreatic ß-cells, skeletal muscle and the liver, leading to changes in metabolic regulation such as severe insulin resistance, hypertriglyceridemia, hepatic steatosis and metabolic syndrome (55,56). 
 
Animal and human studies have revealed that adipose tissue is highly metabolic, having a role in energy balance via secreting hormones that control body weight, food intake and insulin balance (54). One particular discovery is the hormone leptin, primarily produced by adipocytes, that decreases feeding and increases energy expenditure by acting on the leptin receptors (LEPR) in the hypothalamus of the brain (57,58). Leptin’s main role is to regulate long-term energy intakes; however, in periods of starvation or insufficient caloric intake (as seen in "dieting" practices), the loss of adipose tissue results in equal losses of leptin (59-61). This loss of leptin stimulates the brain to release hormones to increase food intake and conserve energy by decreasing energy expenditure, which for some individuals can lead to leptin resistance (59-61). As a result of the discovery of leptin, adipose tissue is no longer viewed only as a storage organ, rather it is crucial in controlling energy balance, appetite, immune function and adapting to changes (weight gain or loss), which is essential for survival (62). Moreover, research on leptin and the endocrine functions of adipose tissue has uncovered further evidence in genetic variations and differences in weight regulation.    
  
Genetic Evidence Affecting Weight
Scientific advances in biological studies have shed light on genetic factors that influence the understanding of body weight/body fat variations. Some individuals are genetically susceptible to increasing weight (adipose tissue) (63,64), which can be largely influenced by family history and ethnicity (65). Large genetic studies by Locke (n=339,224) and Shungin (n=224,459) have found specific genes and alleles responsible for increased weight and body fat traits, primarily found in regions of the brain (melanocortin-4-receptor (MC4R) pathway) associated with controlling hunger (63,66). Specific gene mutations, such as the LEPR, proopiomelanocortin (POMC) and Bardet-Biedl Syndrome (BBS) among many others, have been found to influence appetite control, food intake and energy balance (64,67,68) (See Table 1). This is consistent in both human and animal studies (64,68-70). Various genetic markers conducted in twin, family and adoption studies have concluded that 40-70% of body weight or adipose tissue is genetically based (71) with over 50 genes that are associated with elevated adipose tissue (72). Despite a small proportion (~10%) of single-gene variations (See Table 1) found to date that are responsible for body weight status, multiple gene variations (known as polygenics) are common and in individuals who carry such gene variants, their risk of gaining adipose tissue is 20-30% higher than individuals who do not carry such genes (65).
 
Regardless of one’s predisposition to higher weights or higher percent body fat, a meta-analysis (n≥218,166) concluded that carrying weight-promoting gene variants (i.e. FTO gene) increases the risk of having higher weight by 23% compared to adults who do not carry such genes (73). Thus, individuals who are susceptible to higher body weights may need to have more support to adopt health-related behaviours if their weight is impairing their health (medical, functional and mental health), similar to those with genetic forms of diabetes, heart disease or dyslipidemia. This should not be interpreted as weight loss or healthy eating and physical activity behaviours be promoted solely to individuals with higher body weights, rather that all body sizes and health conditions (regardless of weight) should implement health behaviour changes. Furthermore, health care providers should be aware that genetic influences could account for a portion of their patient/client roster, providing an opportunity to counteract self-blame and accept body diversity.  

Table 1: Rare Genetic Forms of Higher Weight Variations Associated with Increased Appetite 
 
Features
Proopiomelanocortin (POMC) Deficiency (74,75)
  • Severe weight gain beginning early in life (>95 percentile for BMI growth chart) 
  • Excessive eating due to hyperphagia
  • Endocrine abnormalities (adrenocorticotropic hormone deficiency, mild hypothyroidism)
  • Red hair/light skin pigmentation
Leptin Receptor (LEPR) Deficiency (76)
  • Severe weight gain beginning early in life
  • Excessive eating due to hyperphagia
  • Hyperinsulinemia
  • Endocrine abnormalities (hypogonadotropic hypogonadism, hypothyroidism)
  • Early adulthood type 2 diabetes 
Bardet-Biedl Syndrome (BBS) (77,78)
  • Severe weight gain beginning early in life (early onset by age 5 years) 
  • Insatiable hunger (hyperphagia)
  • Cognitive impairment
  • Polydactyly (born with an extra finger or toe)
  • Renal dysfunction 
  • Visual impairment
Alström Syndrome (79) 
  • Severe weight gain beginning early in life (early onset before age 1 year)
  • Short stature in adulthood
  • Progressive visual/auditory impairment
  • Insulin resistance/type 2 diabetes
  • Hyperlipidemia
  • Progressive kidney dysfunction
Review of Energy Expenditure 
Evidence in human physiology states that energy balance is achieved by having equal energy intake to energy expenditure based on the principal law of thermodynamics (4,5). Weight gain is therefore the result of excessive energy intake or inadequate energy expenditure, while weight loss is achieved by reducing energy intake and/or increasing energy expenditure (6,7). Although these principles apply in theoretical contexts, there are considerable interindividual variances in response to changes in energy expenditure (80). 
 
Total energy expenditure (TEE) consists of three components (Table 2):
  1. Resting energy expenditure (REE), also referred to as resting metabolic rate (RMR) or basal metabolic rate (BMR)
  2. Thermic effect of food (TEF), also known as diet-induced thermogenesis (DIT)
  3. Physical activity energy expenditure (PAEE), also known as activity-related energy expenditure (AEE). PAEE is divided further into involuntary energy expenditure called non-exercise activity thermogenesis (NEAT), which includes movements like fidgeting or unplanned activities, and voluntary energy expenditure called exercise activity thermogenesis (EAT), which includes planned activities. Recent discoveries have further understood these components to have a greater impact on weight regulation, which include alterations in energy expenditure in response to weight loss (80,81). This is known as adaptive thermogenesis (AT). 

Table 2: Components of Total Energy Expenditure
Percentage (%) of Total Energy Expenditure (TEE)
Components of Energy Expenditure (EE)
Other Terms/Names
60-70%
Resting Energy Expenditure (REE)
Resting Metabolic Rate (RMR)
Basal Metabolic Rate (BMR)
10-15%
Thermic Effect of Food (TEF)
Diet-induced Thermogenesis (DIT)
20-25%
Physical Activity Energy Expenditure (PAEE)
  • Non-Exercise Activity Thermogenesis (NEAT)
  • Exercise Activity Thermogenesis (EAT)
Activity-related Energy Expenditure (AEE)
Adaptive Thermogenesis (Metabolic Adaptation) 
Body weight (specifically, adipose tissue) is tightly controlled by the MC4R pathway in the brain, which is thought to maintain a level of adipose tissue for evolutionary survival (82-84) and control energy balance (85,86). The MC4R pathway supports eating behaviours by telling other parts of the brain and body when to stop eating, promotes feelings of satiety and assists in controlling adipose tissue (body weight) (87) (See Figure 1). In some individuals with elevated adipose tissue, there are interruptions in the MC4R pathway, which may contribute to elevated appetite, constant hunger and lower ability to burn calories (88,89). In times of energy depletion (as seen in reduced caloric diets), adipose tissue loss is seen as a negative result and compromises survival, initiating a cascade of neurological, endocrinological and metabolic responses that drives the body to restore body fat to its original state (typically, an individual’s highest body weight) by increasing hunger and decreasing fullness (82,90-92). Physiological research has coined this the body’s “set point” (93), in attempts to restore lost weight (body fat).
 
Changes in body weight do not follow a linear line and therefore predictive energy expenditure calculations are not accurate in humans (80,81,94,95). A rigorous systematic review and meta-analysis by Dhurandhar, et al. investigated the compensatory change of energy intake and expenditure and found that decreasing caloric intake to induce a prescribed weight loss will result in less weight loss than estimated given the adaptive thermogenesis (metabolic adaptation) that occurs (81). In fact, when no behavioural interventions are considered, dietary interventions alone account for 12-44% less weight loss than expected and exercise interventions account for 55-64% (81). Furthermore, Schwartz and Doucet (96) reported resting energy expenditure (REE) decreased by ~15 kcal/kg of weight lost, while Polidori and colleagues estimated that appetite (or desire to eat) increased by ~100 kcal/day for every kilogram of weight lost, which challenges sustainable long-term weight loss (97). Both these studies used group mean values (96,97), suggesting considerable interindividual variances.
 
   Figure 1 
Diagram

Description automatically generated
 
Source: Smith A. Neurohormonal effects on obesity. Bariatric Times. 2017;14(11):10-14. (Used with Permission)

Appetite Changes in Response to Weight Change
Evidence supports genetic, biological and physiological aspects of appetite and eating behaviours, energy balance and adipose tissue that impact weight gain (69,90,91,98,99). It has been a popular belief that decreasing energy intake or increasing energy expenditure would result in a negative energy balance resulting in weight loss (7). However, extensive evidence in animal (100,101) and human studies (96,101-103) has shed light that changes in energy balance (positive and/or negative) are affected by afferent neural and hormonal signals from muscles, viscera and adipose tissue directly affecting the hypothalamus (energy control centre) of the brain (98,101).
 
In diet and exercise-induced weight loss studies, anorexigenic hormones (GLP-1, CCK, PYY, etc.) are lower after weight loss (91,102), resulting in individuals feeling less satiated despite adequate nutrient and caloric intake. Simultaneously, the orexigenic hormone ghrelin, which stimulates appetite, is higher after weight loss (90,101,102) and found to be sustained, even when body weight/adipose tissue is regained to its original state. Table 3 reviews the neurohormonal mechanisms and actions after weight loss interventions.

Table 3: Neurohormonal Changes Following Weight Loss Interventions 
Hormones
Location
Mechanism
After Weight Loss* 
After Bariatric Surgery** 
Ghrelin
Secreted from gastric mucosa (stomach) 
Increases hunger
↑ 
Leptin
Produced by adipocytes in response to increased fat reserves
Regulates body fat stores; regulates long-term energy intake; increases POMC/CART signaling in brain (decreases appetite); decreases NPY/AgRP signals (increases appetite)
↓ 
↓ 
PYY  
L-cells of the ileum (small intestine)
Increases satiety (fullness); reduces gastric emptying
GLP-1
L-cells of the ileum (small intestine)
Increases satiety (fullness); regulates energy intake; reduces gastric emptying
CCK
L-cells of the duodenum and jejunum (small intestine)
Increases satiety (fullness); reduces gastric emptying
↑  
(85,99,104,105)
POMC: Pro-opiomelanocortin; CART: cocaine- and amphetamine-regulated transcript; NPY: Neuropeptide Y; AgRP: gouti-related peptide; PYY: Peptide YY; GLP-1: glucagon-like peptide 1; CCK: cholecystokinin
* Weight loss via dietary and/or exercise interventions
**Bariatric surgical procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy
 ↓: decreased; ↑: increased
The physiological effects of bariatric surgery (formerly known as ‘weight loss surgery’), suggest that weight loss is not the primary reason for appetite changes or metabolic improvements as once believed (106,107). Rather, alterations in gastrointestinal anatomy (specific Roux-en-y gastric bypass and sleeve gastrectomy procedures) blunt or reduce orexigenic hormones that would normally increase hunger (ghrelin), irrespective of any significant weight loss (106,108). Anorexigenic hormones (PYY, GLP-1, CCK) that would typically decrease after diet-induced weight loss (making individuals less full) are found to have the opposite effect after bariatric surgery (Table 3) (107,109-111). Refer to references 109 and 112 for a thorough review of gut hormones and their responses from bariatric surgery. These peripheral changes in appetite-modulating hormones affect the hypothalamus of the brain, whereby metabolic adaptation does not appear to affect the body's defense mechanisms to restore adipose tissue loss as strongly compared to diet-induced weight loss (107,110,111); however, long-term studies are mixed and interindividual variances should be considered. 
 
Of note, advances in understanding the physiological mechanisms and neurobiological alterations from these surgical interventions have recommended moving beyond weight loss as an outcome (24). Many organizations have renounced the term 'weight loss surgery' as it misrepresents the actions and mechanisms, replacing it with ‘metabolic or bariatric surgery’, highlighting the above-mentioned findings. This is not universally adopted and therefore is a source of confusion in the public and professional realms (24). Moreover, advances in metabolic and bariatric surgery are expanding the knowledge and opportunities for pharmacological options (113) that target the neurohormonal responses to metabolic adaptation as well as advances in the MC4R pathways of the brain (114). Similar to advances in metabolic conditions (e.g. diabetes, cardiovascular disease and some cancers), pharmacotherapy interventions are targeting biological and physiological mechanisms that treat the root issues affecting inflammation at the cellular level. Further quality research and efficacy is underway and future evidence may identify which interventions may work for long-term use.
 
Conclusion
Weight changes are highly variable, genetically determined and tightly controlled by complex mechanisms in the brain and organs, including adipose tissue. Understanding the physiological drivers that defend against weight loss (specifically adipose tissue and energy regulation) allows clinicians to appreciate that body weight is highly controlled by pathways in the brain and peripheral hormones in the body affecting weight regulation and eating behaviours. 

Patients/clients seeking weight-related support from dietitians should be made aware of the complexity of weight and appetite regulation. Providers should review the risks and benefits of weight loss from interventions that result in caloric deficiency as well as address neurobiological changes that may occur. Despite the physiological effects of weight changes from diet-induced weight loss, many clients/patients have previously sought out weight loss interventions in the past and may already be at risk for long-term weight gain or appetite changes in response to losing weight (already affected by metabolic adaptation). 
 
Dietitians can offer a variety of nutrition interventions that are evidence-based and focus on improving health-related outcomes and quality of life goals (i.e. managing hunger, satiety, cravings, etc.), rather than achieving weight loss ideals (34,115). In 2020, the Medical Nutrition Therapy chapter of the Canadian Adult Obesity Clinical Practice Guidelines reviewed evidence that supports a variety of approaches, emphasizing an individualized client-centred nutrition approach (115). These evidence-based guidelines include the use of non-dieting or weight-inclusive approaches that foster health, emotional well-being and quality of life improvements.

See Additional Content:
 
Advances in genetic, physiological and metabolic research are starting to contribute to the awareness of how harmful messages targeting weight loss or ‘healthy weights’ have had on individuals with larger bodies. However, these advances also provide insight and support for patients/clients that have experienced a lifetime of weight cycling by providing a rationale for how and why body weight and/or appetite is influenced. Dietitians can expand their knowledge of weight physiology and neurohormonal factors that affect appetite and eating behaviours by staying up to date with emerging evidence while providing patients/clients with education and support with goals to reduce weight bias and stigma. 

See Additional Content: Weight Stigma Background.

Resources for Professionals
Clinical practice guidelines, web links and other professional tools and resources can be found under the Weight/Obesity Related Tools and Resources tab. Use the Audience, Country and Language sort buttons to narrow your search.  

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Target Group: All Adults, All children(0-12 yr.), Youth(13-17 yr.)
Knowledge Pathways: Weight/Obesity, Weight/Obesity - Assessment, Weight/Obesity - Dietary Approaches, Weight/Obesity - Dietary Supplements, Weight/Obesity - Pediatric/Paediatric, Weight/Obesity - Pediatric/Paediatric: Prevention
 Last Updated: 2022-06-28


Current Contributors

 

Jennifer Brown - Author

Lindsey Mazur - Author

Helen Croker - Reviewer

Jennifer Brady - Reviewer

Judy Bauer - Reviewer

Maria Ricupero - Reviewer

Natalie Stapleton - Reviewer

Paula Brauer - Reviewer