Aetiology
The reductionist cause of obesity is caloric intake that, over time, is greater than the caloric expenditure. Factors that are associated with this energy imbalance in Western society include genetic predisposition, behavioural dynamics, hormonal disturbances, cultural influences, and environmental circumstances, as described below. These categories overlap, and typically more than one factor is present in a given person.
Genetic: by some estimates, heritable causes of obesity may be present in up to 70% of obese people:[17]
An unequivocal and universal 'fat' gene has not been discovered. Trending scientific opinion is that genetic contribution to obesity may include multiple gene mutations with variable penetrance, mutations in non-coding DNA, epigenetic factors, or alterations in non-coding RNA.
Candidate gene testing and genomic screening have identified a number of genes and/or genetic markers associated with or (in rare cases) causing obesity.[18][19][20]
Behavioural (examples pertain to Western societies):
Mental illness.[30]
Cultural (cultural practices, beliefs about beauty and body image, cuisines, eating habits, and lifestyles contribute to obesity, both within the US and in other countries):[31][32][33]
Can play a role in the aetiology of childhood obesity[34][35]
Contributes to obesity among various minority groups within the US[32]
A factor in some cultures in which obesity is not acknowledged[36]
Contributes to the behavioural factors listed above.
Environmental: further environmental factors associated with obesity, and not mentioned above, include:[37][38][39]
Microbiome of the colon (an emerging area in obesity research which may impact obesity management in the future).[44]
Hormonal (uncommon causes of obesity include acquired disturbances in the hormonal regulation of metabolism):
Pathophysiology
In the typical person, the mechanism which produces an imbalance between energy intake and expenditure primarily involves the regulation of appetite, metabolism, and physical activity. This constellation of processes may also be referred to as energy homeostasis (i.e., the regulation of substrate intake, processing, and utilisation).
Appetite
Dysregulation of substrate intake (i.e., appetite) appears to be central to the pathophysiology of obesity in most people.
Regulation of appetite involves an increasingly complex network of hormones, small molecules, and pathways that are incompletely described.[46][47]
Briefly, appetite regulation consists of two-way communication between the central nervous system (CNS; primarily, the hypothalamus) and peripheral tissues (mainly, the gut organs and adipose tissue).
Hypothalamus
This ventral brain component is the central processing unit for soluble factors (e.g., hormones) from the blood stream (e.g., leptin release from the adipocyte), peripheral neural input (such as gastric distension sending negative feedback to the hypothalamus through vagal afferents), and input from the cerebral cortex (e.g., seeing, smelling, and/or tasting palatable food).
Contains two populations of neurons (described below) in the arcuate nucleus, which have opposing effects on appetite.
Integrates multiple inputs received from the bloodstream, peripheral nerves, and cortex, and delivers signals through the arcuate nucleus back to the CNS and periphery, which stimulate or suppress hunger, modulate metabolism, and influence the level of physical activity.
The most important output or action of the hypothalamus, with respect to obesity, is to regulate appetite.
Leptin
Secreted by adipocytes when substrate is plentiful; secretion decreases when substrate is scarce.
Acts through the hypothalamus as a satiety signal to inhibit appetite and increase substrate utilisation.
Enhances hypothalamic secretion of appetite inhibitors, including pro-hormone pro-opiomelanocortin, and cocaine- and amfetamine-regulated transcript peptide.
Inhibits hypothalamic release of caloric-intake stimulators, including neuropeptide Y, agouti-related protein, and orexin A and B.
Obese people are in a state of relative leptin resistance and do not respond adequately to an increased leptin level.
Gut-derived hunger signals
Ghrelin, secreted primarily by the stomach, acts both directly and indirectly (through the vagus nerve) on the hypothalamus to increase appetite.
Endocannabinoids (which function primarily within the CNS) are also orexigenic (i.e., appetite stimulating).
Triiodothyronine (T3) increases appetite through a central action, but hyperthyroidism typically produces weight loss secondary to increased energy expenditure.
Gut-derived satiety signals
Peptide YY is secreted by the distal intestine and acts on the hypothalamus to decrease appetite.
Both glucagon-like peptide-1 (GLP-1) and oxyntomodulin are produced in the intestine and brain; GLP-1 stimulates pancreatic insulin secretion, and both GLP-1 and oxyntomodulin decrease appetite.
Gastric inhibitory peptide (or glucose-dependent insulinotropic polypeptide [GIP]) is produced in the enteroendocrine K-cells in the duodenum and upper jejunum. Its singular action on satiety is unclear, but it may produce satiety in combination with GLP-1.[48][49]
Cholecystokinin is released from the intestine after feeding and has a long-established function of stimulating gallbladder contraction and pancreatic enzyme secretion; in addition, cholecystokinin acts centrally to inhibit appetite.
Pancreatic polypeptide is released postprandially by pancreatic islet cells and reduces appetite.
In addition to its well-known role in glucose homeostasis, insulin also has a central anorexic effect.
Other circulating molecules that can affect appetite include glucose itself, lipids, and amino acids. These agents all have centrally mediated effects on appetite. For example, severe hypoglycaemia induces food-seeking behaviour, along with other effects. Modest changes in serum glucose; however, have little effect on appetite.
The molecules and pathways that interact to regulate energy homeostasis are incompletely understood. One important but less understood area is how higher cortical functions (e.g., learned behaviours, likes, dislikes) can affect food intake. For example, a person may continue to eat highly pleasing (palatable) food despite being full; in such an instance, the satiety signals have been 'manually over-ridden' by the cerebral cortex.[46] An increased understanding of this and other phenomena of appetite regulation may lead to better medical treatments for obesity.
Studies have identified a phenotype deemed 'metabolically healthy obesity' (MHO) in which people are classified as obese by their BMI, yet have a lower risk of the cardiometabolic abnormalities usually associated with obesity.[50] These individuals tend to have more subcutaneous adiposity relative to visceral adiposity.[50] Several questions still exist regarding the nature of MHO, but it is thought to be a transient phenotype, with metabolic derangements developing as the individual ages. Research suggests cardiovascular risk is elevated in people with MHO compared with metabolically healthy people with a normal weight.[51][52] Appropriate interventions should still be implemented for individuals with the MHO phenotype.
Classification
Obesity classification - updated terminology[4]
Obesity may be subdivided into classes:
Class I: BMI 30.0 to 34.9 kg/m²
Class II: BMI 35.0 to 39.9 kg/m²
Class III: BMI ≥40 kg/m²
Class IV: BMI ≥50 kg/m²
Class V: BMI ≥60 kg/m².
Traditional BMI classification[1][5][6]
Underweight: BMI <18.5 kg/m²
Normal: BMI 18.5 to 24.9 kg/m²
Overweight: BMI 25.0 to 29.9 kg/m²
Obese: BMI ≥30.0 kg/m²
Waist circumference (WC)[7]
The 'threshold WC' is associated with an increased risk of hypertension, diabetes, dyslipidaemia, and the metabolic syndrome.[8][9][10]
Men: WC >102 cm (approx. 40 in)
Women: WC >88 cm (approx. 35 in).
Use of this content is subject to our disclaimer