Pathophysiology of obesity – all about the science to obesity

The complexities of the pathophysiology of obesity

Obesity is a chronic disease caused by a multifactorial aetiology including genetic, metabolic, behavioural, psychological and environmental factors.1 These factors together with the pleasure we derive from food (hedonic factors) – can all influence energy balance, which in turn can lead to weight gain.2 Once established, powerful neuro-hormonal factors effectively defend the body against weight loss, thereby often making obesity a lifelong problem, where weight regain (or relapse) is the rule, rather than the exception.2

Understanding energy imbalance and weight change

Understanding energy balance is crucial to understanding the science to obesity.3 Altered energy balance contributes to the pathophysiology of obesity.3 In individuals with no malabsorption issues, stored energy in the body increases only if total energy intake (from food/ drink consumption) exceeds total body energy expenditure.3

Body energy expenditure can occur through physical activity, basal metabolism and adaptive thermogenesis.3 The body has complex homeostatic mechanisms which attempt to resist both weight loss or gain.3 Overly simplistic views initially determined that obesity resulted from food availability and acts of will.3 However, there are a number of molecular pathways involved in energy imbalance which contribute to obesity. These include the effects of the central nervous system on behaviour such as feeding and physical activity and also the action of the neuroendocrine system which controls the secretion of hormones such as leptin, insulin, oestrogen and growth and thyroid hormones.3

Metabolic adaptations to weight loss

Our bodies are programmed to respond to weight loss with weight regain.2, 4-7 Weight loss alters the body’s homeostatic system,8 which controls appetite, energy intake and energy expenditure, causing the body to increase hunger and lower the metabolic rate – this process is known as metabolic adaptation.8, 9

Effects of obesity on the brain

The central nervous system has a crucial role in obesity and energy balance. Three main areas of the brain contribute to the neurobiology of obesity. These are the hypothalamus, the mesolimbic area and executive function areas.

The hypothalamus and homeostasis

The hypothalamus controls feeding through homeostatic mechanisms. Obesity occurs when there is an imbalance between energy intake and energy expenditure, and the hypothalamus is at the centre of it. Under normal circumstances, long-term energy balance is centrally regulated by the hypothalamus receiving peripheral input.2, 10, 11 The imbalance in energy intake and expenditure can result from changes in these peripheral signals, as well as other factors such as genetic predisposition and the impact of medications.2, 10, 11

The mesolimbic area and hedonic adaptation

The mesolimbic system is the key for non-homeostatic feeding i.e., feeding which does not occur to maintain homeostatic balance but for other reasons including learning, memory and cognitive processes.12, 13 Therefore, it affects feeding based upon hedonic adaptation and past learnt experiences.13 This mesolimbic area can override both physiological hunger and satiety to influence feeding behaviour.13 In particular, palatable food increases dopamine levels in the mesolimbic system.13 Highly palatable food may contain the same number of calories as less palatable food but is more processed with fewer nutritive elements such as fibre and higher levels of sugar and/or salt and/or fat per portion.14 Dopamine is also linked to conditional cues (previous learned experiences) associated with food as a reward and opioid signalling in the mesolimbic area also contributes to this.13 These mechanisms allow food consumption (particularly of palatable foods) to be used as an incentivising reward despite satiety signals.13

The prefrontal cortex and executive functioning

The prefrontal cortex is involved in higher cognitive and executive control functions such as regulating emotions, impulses, desires and cravings including those in relation to food.15 This region can typically counteract the mesolimbic system in its emotional and reward-cue based feeding. However, in stressful situations the prefrontal cortex is dampened down in favour of the mesolimbic system, and this increases automatic survival mechanisms such as food hypervigilance.15 Both acute and chronic stressors increase synamptic branching in the amygdala whilst reducing the synaptic contacts with the prefrontal region.15 In this way, during a chronic stress, a network develops in the brain which favours mesolimbic responses.15 This results in a strong drive to eat which combined with an impaired capacity to inhibit eating can lead to obesity.15

Hormones involved in the science to obesity

The hormones involved in the science to obesity include leptin, insulin, oestrogens, growth hormone and thyroid hormones.3, 16-18 Altered levels of these hormones can contribute to obesity and prevent weight loss in those living with obesity by influencing appetite, metabolism and body fat distribution.

Leptin

Leptin is produced by adipose tissue and acts in the hypothalamus to prevent weight gain by reducing food intake and decreasing the motivational drive for palatable foods.19,20 However, although there are higher levels of circulating leptin in people living with obesity, this does not suppress food intake.3 Food restriction i.e. dieting is a common method used to try and prevent overweight.21 However, the lost weight is often followed by compensatory growth when the restriction ends which can result in overweight.21 A key factor in whether overweight develops may be effectiveness of leptin signal.21

Insulin

Insulin levels correlate with energy balance and levels fall with starvation and rise with obesity.3 Insulin is a key hormone involved in glucose homeostasis through actions on skeletal muscle, liver and adipose tissue.22 In the brain, insulin suppresses neuropeptide Y which promotes weight gain through increased feeding and decreased energy expenditure.3 Therefore, insulin can counteract weight gain.3 When higher circulating insulin levels are necessary to achieve glucose homeostasis, a subject is considered insulin resistant.22 Extensive studies on the molecular aetiology of type 2 diabetes have revealed that low-grade chronic inflammation in those living with obesity mediates insulin resistance which can lead to type 2 diabetes.23

Oestrogens

Menopausal women are three times more likely to develop obesity compared to premenopausal women.16 Decreased levels of oestrogen play an important role in the development of obesity in menopausal women.16 The absence of oestrogen causes a variation in the lipid profile of post-menopausal and also causes predominant abdominal fat accumulation.16 Indeed, a meta-analysis of over 100 randomised trials in menopausal women has analysed the effect of hormone replacement therapy (HRT) containing oestrogen on components of metabolic syndrome found HRT containing oestrogen increased lean body mass, reduced abdominal fat and improved insulin resistance.16

Growth and thyroid hormones

Growth hormone stimulates growth in children and in adults. Its main role is to regulate metabolism.24 Growth hormone secretion, both spontaneous and that evoked by stimuli, is blunted in obesity.17 The pathophysiologic role of growth hormone in obesity is yet to be fully understood, however administering growth hormone has been linked to weight loss and metabolic efficacy of lean body mass in those living with obesity.17 Similarly, thyroid hormones are consistently dysregulated in obesity. Sub-clinical hypothyroidism with elevated TSH and normal peripheral thyroid hormone concentration has been consistently found in obese subjects.18

Maintaining weight loss is challenging

A review of 14 long-term studies showed that one to two thirds of people with obesity regained more weight after weight loss achieved by dieting.25 Furthermore, the ACTION IO study* found that  81% of people with obesity have engaged in one or more serious weight loss attempts; however, only 11% were able to maintain a 5% weight loss for one year or more. 26

*The Awareness, Care and Treatment in Obesity MaNagement – an International Observation (ACTION IO) Study is the first international study to investigate barriers to obesity management among people with obesity and healthcare professionals in 11 countries worldwide (Australia, Chile, Israel, Italy, Japan, Mexico, Saudi Arabia, South Korea, Spain, UAE, UK). A total of 14,502 people with obesity and 2,785 healthcare professionals completed the survey.26

Visual adapted from Mann T, Tomiyama AJ, Westling E, Lew AM, Samuels B, Chatman J. Medicare's search for effective obesity treatments: diets are not the answer. Am Psychol. 2007;622(3):220–233.

Watch the video below to find out why it is so difficult to keep off the weight we have lost.

Effective and lasting obesity management

Maintaining weight loss is challenging for people living with obesity, and findings such as from the ACTION IO study* show that obesity isn’t about willpower.26 To understand what the effective strategies for obesity management are, we need to consider, physiological, psychological and biological factors of obesity. Although diet modification and exercise continue to be key in the management of obesity, increasingly patients require pharmacological adjuncts in order achieve or maintain weight loss.20 It is also crucial to understand the multiple systems involved in the pathophysiology of obesity and interventions to tackle these could be essential in providing lasting weight loss. Download our ‘Losing weight is hard’ PDF handout below to help educate your patients about the potential challenges of effective weight management and share it with medical colleagues to support their daily practice. 

References
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7. Rosenbaum M, Kissileff HR, Mayer LE, Hirsch J, Leibel RL. Energy intake in weight-reduced humans. Brain Res. 2010;1350:95-102.
8. Greenway FL. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes (Lond) . 2015;39(8):1188-96.
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10. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-604.
11. Heymsfield SB, Wadden TA. Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med. 2017;376(15):1492.
12. Naef L, Pitman KA, Borgland SL. Mesolimbic dopamine and its neuromodulators in obesity and binge eating. CNS Spectr. 2015;20(6):574-83.
13. Liu CM, Kanoski SE. Homeostatic and non-homeostatic controls of feeding behavior: Distinct vs. common neural systems. Physiol Behav. 2018;193(Pt B):223-31.
14. Massicotte E, Deschenes SM, Jackson PL. Food craving predicts the consumption of highly palatable food but not bland food. Eat Weight Disord. 2019;24(4):693-704.
15. Yau YH, Potenza MN. Stress and eating behaviors. Minerva Endocrinol. 2013;38(3):255-67.
16. Lizcano F, Guzman G. Estrogen Deficiency and the Origin of Obesity during Menopause. Biomed Res Int. 2014;2014:757461.
17. Scacchi M, Pincelli AI, Cavagnini F. Growth hormone in obesity. Int J Obes Relat Metab Disord. 1999;23(3):260-71.
18. Bandurska-Stankiewicz E. Thyroid hormones – obesity and metabolic syndrome. Thyroid Research. 2013;6.
19. Kanoski SE, Hayes MR, Skibicka KP. GLP-1 and weight loss: unraveling the diverse neural circuitry. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R885-95.
20. Gonzalez Jimenez E. Obesity: etiologic and pathophysiological analysis. Endocrinol Nutr. 2013;60(1):17-24.
21. Zhao Y, Chen LB, Mao SS, Min HX, Cao J. Leptin resistance was involved in susceptibility to overweight in the striped hamster re-fed with high fat diet. Sci Rep. 2018;8(1):920.
22. Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev. 2018;98(4):2133-223.
23. Kim J, Lee J. Role of obesity-induced inflammation in the development of insulin resistance and type 2 diabetes: history of the research and remaining questions. Ann Pediatr Endocrinol Metab. 2021;26(1):1-13.
24. Olarescu NC, Gunawardane K, Hansen TK, Moller N, Jorgensen JOL. Normal Physiology of Growth Hormone in Adults. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., editors. Endotext. South Dartmouth (MA). 2000.
25. Mann T, Tomiyama AJ, Westling E, Lew AM, Samuels B, Chatman J. Medicare's search for effective obesity treatments: diets are not the answer. Am Psychol. 2007;62(3):220-33.
26. Caterson ID, Alfadda AA, Auerbach P, Coutinho W, Cuevas A, Dicker D, et al. Gaps to bridge: Misalignment between perception, reality and actions in obesity. Diabetes Obes Metab. 2019;21(8):1914-24.

HQ21OB00154, Approval date: September 2021

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ContentsThe complexities of the pathophysiology of obesityUnderstanding energy imbalance and weight changeMetabolic adaptations to weight lossEffects of obesity on the brainHormones involved in the science to obesityMaintaining weight loss is challengingEffective and lasting obesity management

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