Understanding the pathophysiologic pathways that underlie obesity and options for treatment

ABSTRACT

Introduction

Obesity is a chronic, multifactorial condition with devastating health consequences. It was thought that obesity could be controlled with discipline and lifestyle changes, but we now know that the underlying pathophysiology is a dysregulation of the body’s energy balance system, controlled by a complex interplay of neural, hormonal, and metabolic pathways. Recognizing obesity as a chronic disease places a greater responsibility on all health care professionals to screen and identify patients at risk and develop long-term tailored treatment plans.

Areas covered

This narrative review describes the central and peripheral pathways regulating obesity, the factors contributing to its development and how to effectively manage this disease.

Expert opinion

Obesity is a disease with pathophysiologic mechanisms and should be treated accordingly to reduce the significant risk of morbidity and mortality. Lifestyle interventions remain the cornerstones of treatment; however, these measures alone are rarely enough for long-term maintenance of weight loss. Additional interventions, such as pharmacotherapy or bariatric surgery, are indicated for many patients and should be recommended. Treatment considerations should include assessment of comorbidities or risk factors, as many anti-obesity agents and bariatric surgeries also have beneficial effects on other weight-associated comorbidities.

Plain language summary: This plain language summary highlights information from a recent scientific article about obesity. Obesity is a disease that leads to excess accumulation of body fat that may negatively affect health. People can check if they have obesity by measuring their body mass index (BMI for short). The BMI is a screening tool to see if you are at risk of obesity. Obesity is defined as a BMI of 30 kg/m2 or higher with lower cut-offs in Asian populations. Obesity is a chronic health condition that leads to a shorter life span. People with obesity have a higher chance of having other health conditions, such as type 2 diabetes, fatty liver disease, heart disease, kidney problems, osteoarthritis, and some types of cancer. It can be hard for people with obesity to lose weight for various reasons. The aim of this article is to help doctors who treat people with obesity understand more about the causes for obesity, as well as the available treatment options, which include lifestyle changes, medicines, and for some people, weight loss surgery.

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© 2021 Boehringer Ingelheim. Published by Informa UK Limited, trading as Taylor & Francis Group.

KEYWORDS:

• Bariatric surgery
• energy homeostasis
• gut hormones
• hypothalamus
• lifestyle interventions
• obesity
• type 2 diabetes
• weight loss

1. Introduction

Obesity is a chronic, multifactorial disease associated with devastating health consequences and a large economic burden on a national and global level [1]. It increases the risk of developing type 2 diabetes (T2D), cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), kidney disease, obstructive sleep apnea, gout, osteoarthritis [2], multiple cancers (including liver, pancreas, kidney, and cervical cancer) [3], and contributes to a shortened life span [2]. The World Health Organization (WHO) classifies obesity as a body mass index (BMI) ≥30 kg/m² and overweight by a BMI 25.0–29.9 kg/m², with lower BMI cutoffs in Asian populations [4].

The age-adjusted prevalence of obesity in the United States among adults has increased from approximately 30% in 1999–2000 to about 42% in 2017–2018 [5]. This is based on data from the National Health and Nutrition Examination Survey (NHANES) for the years 1999–2018. Prevalence is projected to reach 45% by 2030 [6]. Persons with obesity face many clinical issues, including sleep apnea, respiratory problems, joint pain and impaired mobility, as well as social stigma [7]; additionally, work productivity and earnings potential are reduced, adversely affecting job opportunities and socioeconomic status. Individuals with obesity also experience greater stress levels and loneliness, leading to a lower quality of life.

Obesity was once regarded as a behavioral disorder that could be controlled with discipline and lifestyle changes; therefore, exercise and dieting became the mainstays of obesity treatment to address excess nutrient intake and physical inactivity. Consequently, people who could not lose weight or regained weight lost were labeled as lazy, unmotivated, and undisciplined by their families, employers, and physicians. This approach of placing all responsibility for weight loss on the individual has not served persons with obesity well, leading to feelings of guilt and inadequacy. However, it is now understood that neither behavior nor the environment are responsible for obesity independent of the complex human energy balance system. The underlying pathophysiology of obesity is a dysregulation of the body’s energy balance, which is controlled by a complex interplay of neural, hormonal, and metabolic pathways [8]. Contributing factors include genetic susceptibility, epigenetics, hormones, medication use, stress, sleep disturbance, and mental health. Environmental influences, such as an increasingly sedentary lifestyle with reduced physical activity both in the workplace and during leisure time coupled with an abundance of nutrient-dense and highly palatable food, present a strong risk factor for obesity [9–11].

In 2008, The Obesity Society (TOS) published a paper supporting the position that obesity should be declared a disease [12]. In 2011, the American Board of Obesity Medicine (ABOM) was established to create a unified certification process for physicians in the field of obesity medicine; those who complete the ABOM certification are Diplomates of the ABOM. In 2013, the American Medical Association declared obesity as a disease; this was followed by a report by the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines and TOS that also designated obesity as a disease [13,14], acknowledging an associated underlying pathology. The designation of obesity as a chronic disease and its increasing prevalence place a greater responsibility on all health care professionals (HCPs) to screen and identify patients at risk and develop long-term tailored treatment plans. This article reviews the pathophysiology of obesity, the challenges of long-term weight management, and available treatment and management options for patients with obesity.[9–11]

2. Pathophysiology of obesity

In simplistic terms, obesity is the result of more energy taken in as calories consumed than energy expended. However, ongoing research shows that energy homeostasis is a far more complicated process than just passive accumulation of excess calories, involving both central and peripheral pathways and their complex interplay [15]. Steady-state body weight is determined by different factors that include genetic, homeostatic, environmental, and behavioral components.

2.1. Central pathways for energy regulation

2.1.1. Hypothalamus

Signals involved in the homeostatic regulation of food intake, energy balance, and body weight are integrated centrally in the hypothalamus, specifically in the arcuate nucleus, where energy homeostasis is regulated via two opposing systems [16]. The orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY)-expressing ‘hunger’ neurons are activated during times of a low energy balance, increasing appetite and food intake, and decreasing energy expenditure. This is in part mediated by the action of two hormones, leptin and insulin, in which plasma levels are reduced in the fasting state, releasing inhibitory actions on these neurons. Adjacent to the AgRP neurons are the anorexigenic pro-opiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-expressing neurons, which decrease food intake and increase energy expenditure [16]. The POMC-expressing neurons are stimulated by leptin and release the neuropeptide α-melanocyte stimulating hormone (α-MSH), which results in reduced food intake. Thus, following negative energy balance and fat loss that reduces leptin levels, AgRP neurons are activated, whereas POMC neurons are inhibited, increasing food intake and reducing energy expenditure. Both systems are also influenced by afferent signals from the gut, adipose tissue, liver, and pancreas to form a complex system of energy homeostasis (Figure 1) [17]. Additionally, the hypothalamus integrates signals from hedonic pathways in the corticolimbic system, which are associated with food palatability [18]. The corticolimbic system includes the hippocampus, amygdala, dorsolateral prefrontal cortex, and anterior cingulate cortex, which process reward, cognition, and executive functions [18]. This system interfaces with the environment and is intricately connected to the hypothalamus providing emotional, cognitive, and executive support for eating behavior [18]. Studies have shown that the neurology of reward, economics, and decision-making are an important determinant of food intake, and that many of these neural processes occur outside of our awareness [18]. In fact, hedonic pathways can override the homeostatic system, increasing the drive to eat ultra-processed foods despite physiologic satiety [19].

Figure 1. Hormonal and neural pathways regulating food intake [17]. AgRP: agouti-related peptide, α-MSH: α-melanocyte-stimulating hormone, GHsR: GH secretagogue receptor, INSR: insulin receptor, LEPR: leptin receptor, MC4R: melanocortin receptor type 4, NPY: neuropeptide Y, POMC: pro-opiomelanocortin, PYY: peptide YY, Y1R: Y1 receptor, Y2R: Y2 receptor.

From Apovian CM, Aronne LJ, Bessesen DH Pharmacological management of obesity: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:342–362, licensed under Creative Commons CC-BY-NC-ND.

Several neurotransmitters in the brain play a major role in the reward pathways, including serotonin 5-hydroxytryptamine [5-HT], dopamine, and norepinephrine (NE). Serotonin is produced in the raphe nuclei of the brainstem [20], and increased 5-HT signaling is associated with decreased appetite and food intake, whereas decreased signaling induces hyperphagia and weight gain. 5-HT 1B receptor activation inhibits AgRP/NPY neurons, while 5HT-2C receptor activation stimulates POMC neurons. Dopamine is produced in the ventral tegmental area (VTA) and substantia nigra and relays the rewarding aspects of food-associated stimuli. In obesity, there is decreased dopaminergic signaling, which may promote the overconsumption of food to compensate for the reduced reward sensation [20]. NE is produced in the locus coeruleus and acts in the hypothalamus by stimulating eating via the dorsal pathway and inhibiting eating via the ventral pathway. In the paraventricular nucleus, NEα1 receptor activation suppresses feeding, whereas NEα2 receptor activation stimulates feeding.

The hypothalamus also integrates peripheral signals from the gastrointestinal (GI) tract, pancreas, adipose tissue, liver, and muscle that provide information on nutrient status and energy stores [19]. Primary hormonal signals from the GI tract also act on the hindbrain and nucleus of the tractus solitarius (NTS). These signals include the orexigenic hormone ghrelin as well as the anorexic hormones glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and leptin, which are part of a feedback loop between the brain and the periphery.

2.2. Peripheral pathways for energy regulation

2.2.1. Gut hormones

Gut hormones are well recognized as regulators of GI motility and digestion. In addition, these hormones, which are secreted by endocrine cells in the stomach, gut, and pancreas, modulate food intake and thus contribute to energy homeostasis [20]. Anorexigenic intestinal hormones such as GLP-1, PYY, and cholecystokinin (CCK) are secreted in response to food intake and promote satiety. Obesity is associated with attenuated activity of anorexigenic hormones. Ghrelin is produced in the stomach and is the only known orexigenic (i.e. hunger) hormone. Its levels increase during times of fasting and it stimulates appetite and promotes eating. Fasting ghrelin levels are inversely correlated with BMI and obesity is associated with reduced postprandial ghrelin suppression. Therefore, disturbances in ghrelin suppression and/or increases in anorexigenic hormones can affect the energy balance. Gut hormones have been investigated as potential therapeutic agents in obesity; liraglutide, a GLP-1 receptor agonist, was approved by the US Food and Drug Administration (FDA) in 2014 as an anti-obesity agent.

2.2.2. Leptin

Leptin is mainly secreted by white adipocytes and its levels correlate with fat mass, thus, in persons with obesity, leptin levels are elevated. Leptin mediates most of its actions in the hypothalamus. As mentioned earlier, leptin activates anorexigenic POMC neurons and suppresses the activity of orexigenic AgRP neurons chronically and is not an acute satiety signal. Leptin also counterbalances the effects of ghrelin. Increased leptin levels suppress appetite and increase energy expenditure. The vast majority of persons with obesity appear to be leptin resistant, making leptin administration ineffective for treating common forms of obesity. However, in those with congenital leptin deficiency, recombinant human leptin (metreleptin) has been successfully administered [7].

2.2.3. Adipocytes

Adipocytes play an important role in peripheral regulation of energy balance. White adipose tissue, the main cell type found in human fat, is characterized by one large intracellular lipid droplet that stores energy in the form of triglycerides and cholesterol esters. Adipocytes also synthesize and secrete adipokines, such as adiponectin and leptin, which are instrumental in energy homeostasis [21]. The main function of brown adipose tissue (BAT), which is composed of multiple small lipid droplets, is the dissipation of energy through uncoupled respiration, thus producing heat. This process is mediated by the uncoupling protein-1 (UCP-1) found in the mitochondria. A third type of adipocyte is referred to as beige or brite, with morphology between white and brown adipose tissue. Beige adipocytes can transform into the thermogenic or storage phenotype depending on the environment [21]. BAT is important in newborns to help keep them warm, but the amount of BAT rapidly decreases by childhood and continues to decline with age; in most adults, BAT is detectable mainly in the supraclavicular, paravertebral, and mediastinal regions. BAT is activated in patients with pheochromocytoma and paraganglioma, most likely due to a systemic excess of catecholamines [22]. Both white and brown adipose tissue have been suggested as therapeutic targets for treatment of obesity, T2D, and other metabolic conditions. It has been widely accepted that cold exposure increases BAT activity; the effects of physical activity, capsaicin, and eicosapentaenoic acid, an omega-3 fatty acid, are being considered. Pharmacologic targets for activation of BAT in the treatment of obesity are currently under investigation, including peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists and retinoids, however, much of this research is still in the in vitro stage. In contrast, mirabegron, a β3-adrenergic receptor agonist (β3-ARA) approved for the treatment of overactive bladder, has been studied in humans. Preclinical results suggest that β3-ARAs could also improve obesity-associated metabolic disease by increasing BAT thermogenesis, white adipose tissue lipolysis, and insulin sensitivity. A small study of 14 women (100 mg mirabegron XR for 4 weeks) demonstrated increased BAT metabolic activity as well as improved insulin sensitivity [23].

2.3. Other pathways of energy regulation

2.3.1. Microbiome

Muscle and the microbiome of the gut play important roles in regulating energy expenditure. The term microbiota refers to a complex and dynamic ecosystem consisting of trillions of bacteria within our gut. This community of microbes acts as an organ with many metabolic, immunologic, and endocrine-like actions that influence our health [24]. Imbalances in the microbiome have recently been associated with several non-intestinal disease states, including diabetes, CVD, and obesity [24]. Microbiota can influence metabolism, adiposity, energy homeostasis, and energy balance as well as central appetite and food reward signaling, which together have crucial roles in obesity. Approximately 90% of the intestinal microbiome is composed of the phyla Firmicutes (gram positive) and Bacteroidetes (gram negative): in obesity, Firmicutes is proportionally increased compared to Bacteroidetes. Environmental factors, such as antibiotic use early in life, can alter the microbiome and contribute to obesity [25]. One study showed that repeated antibiotic use between birth and 4 years of age was associated with a higher BMI in children and increased the likelihood of obesity [25].

2.3.2. Muscle

Skeletal and cardiac muscle plays a central role in metabolic syndrome and is a regulator of total body mass and energy consumption [26]. The loss of skeletal muscle with aging, sarcopenia, can lead to a reduction in energy expenditure and greater tendency to accumulate adipose tissue (called sarcopenic obesity). High levels of triglycerides, free fatty acids, and glucose, coupled with physical inactivity, affect skeletal and cardiac muscle metabolism. As striated muscles adapt to increased substrate availability, energy homeostasis is altered, contributing to the onset of obesity and diabetes [26].

3. Physiologic adaptations to weight loss

The complex interplay of pathways contributing to energy homeostasis is designed to maintain body weight in times of low nutrient availability. Thus, diet-induced weight loss triggers biological adaptations that favor weight gain, such as increased appetite, reduced satiety signals, and altered food preferences and cravings. For example, weight loss has been shown to lead to increased secretion of the hunger hormone ghrelin and a reduction in the postprandial secretion of satiety peptides such as GLP-1, PYY, and CCK [27]. Additionally, weight loss is accompanied by a reduced resting metabolic rate that can be greater than would be expected based on changes in body composition. It is thought to persist following weight loss, despite weight being regained. This phenomenon, called ‘metabolic adaptation’ or ‘adaptive thermogenesis,’ acts to counter weight loss and is coordinated by multiple hormonal changes, most notably a reduction in serum leptin, and contributes to weight regain [28,29].

4. Causes of obesity

Numerous factors contribute to obesity, including environmental, neurological, endocrine, medication-induced, psychological, and behavioral causes (Table 1) [17]. Not all people living in an obesogenic environment become obese, which suggests that there are underlying genetic mechanisms in place [17].

Table 1. Causes of obesity [17]

Primary causes	Examples
Genetic
Monogenic	MC4 receptor mutations Leptin deficiency POMC deficiency
Secondary causes	Examples
Hypothalamic	Brain injury Brain tumor Cranial irradiation Syndromes: Froehlich Prader-Willi Bardet-Biedl Cohen Alström
Endocrine	Hypothyroidism Cushing’s syndrome Growth hormone deficiency Pseudohypoparathyroidism
Psychological	Stressors Depression Eating disorder
Environmental/behavioral	Sedentary lifestyle Insomnia Endocrine disruptors Stress
	Emotional eating High-calorie diet Limited access to nutritious food
Drug-induced	See Table 2

MC: melanocortin, POMC: pro-opiomelanocortin.

Table 2. Medications for people with multiple comorbidities and how they affect body weight [39]

	Weight gain	Weight neutral	Weight loss
Antidiabetes	Insulin Thiazolidinediones Sulfonylureas Meglitinides	α-Glucosidase inhibitors Bromocriptine Colesevelam DPP-4 inhibitors	GLP-1 receptor agonists Metformin Amylin analogues (Pramlintide) SGLT2 inhibitors
Antihypertensive	α-Adrenergic blockers β-Adrenergic blockers (atenolol, metoprolol, nadolol, propranolol) (dyslipidemia, insulin resistance, ↓metabolic rate by up to 10%)	ACE inhibitors ARBs (provide renal protection) β-Adrenergic blockers (carvedilol, nebivolol) CCBs Thiazides (dyslipidemia, insulin resistance)
Antidepressant	TCAs (amitriptyline, doxepin, imipramine, nortriptyline) MAOIs Mirtazapine SSRI (paroxetine) Lithium	SSRIs (fluoxetine, sertraline)	Bupropion (↓appetite and food cravings)
Antiseizure	Gabapentin Pregabalin Valproic acid Vigabatrin	Amotrigine Levetiracetam Phenytoin Lamotrigine	Topiramate Zonisamide
Antipsychotic	Clozapine Olanzapine	Aripiprazole Ziprasidone
Contraceptive	Medroxyprogesterone	Copper IUD
Migraine therapy	β-adrenergic blocker (propranolol)	Botulinum toxin Calcium channel blockers	Topiramate
Hormone therapy	Corticosteroids

ACE: angiotensin-converting enzyme, ARB: angiotensin receptor blocker, CCB: calcium channel blocker, DPP-4: dipeptidyl peptidase-4, GLP-1: glucagon-like peptide-1, IUD: intrauterine device, MAOI: monoamine oxidase inhibitor, SGLT2: sodium glucose co-transporter 2, SSRI: selective serotonin receptor inhibitor, TCA: tricyclic antidepressant.

4.1. Genetic causes

Twin and family studies have shown that BMI heritability is high (~40%–70%) [30,31]. More than 10 rare monogenic forms of obesity are known, including deficiencies in leptin or the leptin receptor, the melanocortin 4 (MC4) receptor, POMC, and proprotein convertase subtilisin/kexin type 1 (PCSK1), all mainly located in the hypothalamus where energy homeostasis and satiety are regulated [30]. Congenital leptin deficiency is associated with undetectable leptin levels and leads to early-onset severe obesity, hyperphagia, and altered immune function; it can be treated with metreleptin [30]. Heterozygous mutations in the MC4 receptor gene are currently the most common cause of obesity in children, appearing in 2% to 5% of those with severe obesity [31]. Polymorphisms of the fat-mass and obesity-associated (FTO) gene have been associated with obesity in children and adults; the effect of FTO on obesity may be influenced by environmental factors and lifestyle [32]. Polygenic forms of obesity are most common and highlight the complexities of energy and metabolic regulation and the interplay of neurohormonal pathways.

4.2. Epigenetic causes

Epigenetics is the study of heritable changes that affect gene function, via DNA methylation and histone modifications, but do not change the DNA sequence. Epigenetic mechanisms, the interaction between the environment and the genome, play a role in energy homeostasis [30,33]. In epigenome-wide association studies, DNA modifications in tissues relevant for energy regulation, such as skeletal muscle and adipose tissue, have been shown to occur in response to high-fat diets and exercise, and may subsequently affect weight loss or gain [30]. Additionally, findings from several studies demonstrate altered DNA methylation in individuals with obesity compared with those without obesity. Of note, weight loss associated with Roux-en-Y gastric bypass (RYGB) surgery alters the epigenome in adipose tissue, skeletal muscle, and blood. Early on, maternal obesity and environmental stressors can lead to epigenetic alterations during pregnancy and these changes can influence fetal phenotype and increase the risk of metabolic disorders in later stages of life [34]. Intrauterine growth retardation leads to reduced birth weight and the development of metabolic diseases such as T2D in adulthood [35].

4.3. Environmental causes

A multitude of other factors, such as insomnia, stress, mental health conditions, endocrine disorders, environmental endocrine disruptors, and medications can contribute to obesity by affecting energy homeostasis. Sleep is important for neuroendocrine function. Lack of sleep has been shown to decrease glucose tolerance and insulin sensitivity, leading to decreased levels of leptin, increased levels of ghrelin, and increased appetite [36]. Stress as well as depression and anxiety may cause people to eat more comfort foods that are high in fat, salt, and sugar. Moreover, chronic cortisol hypersecretion as a result of stress leads to fat storage in the abdominal region (visceral fat), which is known to be associated with the development of CVD, including coronary heart disease and ischemic stroke. Thyroid hormones regulate basal metabolism, thermogenesis, and play an important role in energy homeostasis. Thyroid dysfunction is associated with changes in body weight and composition, body temperature, and total and resting energy expenditure independent of physical activity [37]. Endocrine disruptors, such as bisphenol A (BPA) and perfluorinated chemicals (PFCs), have been linked to obesity because of their potential to mimic or alter receptor signaling of endogenous hormones, including estrogen, testosterone, and thyroid hormone [15]. Some endocrine disruptors can act directly on adipocytes to promote adipogenesis [15]. A comprehensive review of these agents is provided in a scientific statement by the Endocrine Society [38]. Finally, weight gain may result from some medications, but can be averted or ameliorated by tailoring medications based on the patient’s medical history and lifestyle [39]. Table 2 shows how glucose-lowering, antihypertensive, and antidepressant agents affect body weight [39].

5. Management of obesity

5.1. Guidelines

A number of current obesity treatment guidelines are available; however, as they are not completely aligned on their strategies, confusion for HCPs may ensue. Nonetheless, the guidelines do provide recommendations for what to assess in patients with obesity and how to advise appropriate treatment options. The 2013 AHA/ACC/TOS guidelines are BMI-centric, but do not provide ethnicity-specific BMI cutoff points. Like previous guidelines, they recommend that for individuals with a BMI ≥30 kg/m² or BMI ≥27 kg/m² with ≥1 obesity-associated comorbidity, pharmacotherapy can be considered as an adjunct to comprehensive lifestyle intervention. Bariatric surgery can be considered for those with a BMI ≥40 kg/m² or ≥35 kg/m² with ≥1 obesity-associated comorbidity [13,14]. They have a somewhat limited approach to strategies for weight management based on the clinical trials and treatment options that were available when the guidelines were written. The more recent 2015 guidelines from the Endocrine Society [2,17] focus on the data supporting the use of medications for weight loss and are meant to complement the AHA/ACC/TOS guidelines. The 2016 American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines [40] focus on prevention and improvement of obesity-associated complications through weight management; they provide a grading system for disease severity, with severity of comorbidities determining intensity of treatment. There have also been suggestions to classify obesity as an adiposity-based chronic disease. [41] The most recent guidelines were issued in August 2020 by Obesity Canada and the Canadian Association of Bariatric Physicians and Surgeons [42]. An update to their 2006 guideline, the new guidance incorporates the perspectives of people with experience living with obesity as well as experts in the management of obesity and takes a patient-centric approach. They provide specific recommendations on pharmacotherapy to achieve weight loss for individuals with BMI ≥30 kg/m² or BMI ≥27 kg/m² with adiposity-associated complications, in conjunction with medical nutrition therapy, physical activity, and psychological interventions. Additionally, these guidelines recommend pharmacotherapy for maintaining the weight loss that has been achieved. Of note, none of the above obesity guidelines include ethnicity-specific BMI cutoff points, although the WHO provides these for the definition of obesity [4] and the American Diabetes Association (ADA) uses them to determine eligibility for bariatric surgery [43]. Inclusion of ethnicity-specific BMI cutoffs may need to be considered in the future due to predisposition to metabolic disease in certain ethnic groups at lower BMI classes.

5.2. Lifestyle interventions

All guidelines recommend lifestyle interventions (dietary changes, increased physical activity, behavior modification) as a cornerstone of obesity treatment, since there is strong evidence from several clinical trials that these efforts can be successful. The randomized Look AHEAD trial compared the effectiveness of intensive lifestyle intervention (ILI) versus usual care in >5000 people with overweight or obesity over 8 years [44]. The trial is significant because it was the longest and largest study of its kind.

The greatest weight loss was achieved after 1 year (average 8.6% of body weight vs 0.7% in the control group); after 8 years of ILI weight loss was maintained at ≥5% of baseline body weight [44,45]. Weight changes were associated with a number of improved CVD risk factors, such as blood pressure, hyperlipidemia, and blood glucose levels. In addition, ILI was associated with many other health benefits, including improved biomarkers of glucose and lipid control, less sleep apnea, lower liver fat, less depression, improved insulin sensitivity, less urinary incontinence, less kidney disease, reduced need for diabetes medications, maintenance of physical mobility, improved quality of life, and lower costs. The incidence of CVD events, such as myocardial infarction and stroke, were not reduced. However, in a secondary analysis of the Look AHEAD data, persons who lost >10% body weight in the first year had a significant (~20%) reduction in CVD endpoints, suggesting an association between the degree of weight loss and CVD incidence.[46]

The Diabetes Prevention Program (DPP) [47–49] was a randomized trial that evaluated ILI or pharmacotherapy (metformin) versus placebo to prevent or delay the onset of diabetes in >3000 individuals with impaired glucose tolerance and a BMI ≥25 kg/m² [47]. The goals for the participants assigned to the ILI group were to achieve and maintain a weight reduction of ≥7% of initial body weight through a healthy low-calorie, low-fat diet and to engage in physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week. The average follow up was 2.8 years [47]. Results showed that 50% of participants in the ILI group achieved the goal of ≥7% weight loss at 24 weeks, and 38% had ≥7% weight loss at the time of the most recent visit. Furthermore, the incidence of diabetes was reduced by 58% (ILI) and 31% (metformin) versus placebo [47]. The DPP Outcomes Study [48] followed participants for a further 10 years, at which time the average weight loss had decreased to ~2% below baseline. However, the onset of T2D was still significantly delayed (compared with the original placebo group) and CVD risk factors were significantly improved [48]. Therefore, prevention of T2D and improvement of CVD risk persisted for 10 years, despite diminished weight loss. These trials have shown that although lifestyle modifications can be effective in producing short-term weight loss, they are not effective in providing long-term weight maintenance, due to metabolic adaptations. A more holistic, evidence-based approach for effective obesity treatment is necessary.

5.3. Pharmacotherapy

Pharmacotherapy is indicated for patients with a BMI ≥30 kg/m² or ≥27 kg/m² with ≥1 obesity-associated comorbidity [50]. Several medications with diverse mechanisms of action are approved in the United States for weight management (Table 3) [16]. Most agents act centrally by targeting appetite and work primarily in the arcuate nucleus to stimulate POMC neurons, promoting satiety [17], although effects on cravings and energy expenditure have been observed as well. The exception is orlistat, the only peripherally acting agent, which blocks gastric and pancreatic lipases, preventing the absorption of dietary fat. A systematic review and meta-analysis compared weight loss and adverse events (AEs) among drug treatments in >29,000 patients with obesity in 28 clinical trials [51]. These included 27 two-group trials comparing active intervention to placebo (orlistat, 16 trials; lorcaserin, 3 trials; naltrexone-bupropion, 4 trials; phentermine-topiramate, 2 trials; liraglutide, 2 trials) and one three-group trial comparing liraglutide and orlistat to placebo. All agents met the FDA regulatory requirement of ≥5% weight loss at 52 weeks versus placebo [51] (the FDA requested lorcaserin to be withdrawn from the market in 2020 due to increased occurrence of cancers, including pancreatic, colorectal, and lung) [52]. Phentermine-topiramate (odds ratio [OR], 9.1) was associated with higher odds of achieving ≥5% and ≥10% weight loss compared with all other agents, and there was no difference in the odds of AE-associated discontinuations among phentermine-topiramate, liraglutide, and naltrexone-bupropion. Liraglutide (OR, 5.09) was associated with higher odds of achieving ≥5% and ≥10% weight loss compared with orlistat, lorcaserin, and naltrexone-bupropion, but was associated with higher odds of discontinuation due to AEs. More recently, another GLP-1 agonist – once-weekly semaglutide 2.4 mg – was approved for chronic weight management in patients with obesity. Results from the STEP clinical trial program demonstrated that in patients with obesity but without type 2 diabetes, semaglutide 2.4 mg was associated with a sustained clinically relevant reduction in body weight compared with placebo; estimated treatment difference versus the placebo group was –12.7 kg (95% CI, –13.7 to –11.7) in STEP 1 (weight loss to week 68: semaglutide –15.3 kg vs placebo –2.6 kg) [53], and –10.6 kg (95% CI, –12.5 to –8.8) in STEP 3 (weight loss to week 68: semaglutide –16.8 kg vs placebo –6.2 kg) [54]. Similarly, in patients with obesity and type 2 diabetes, semaglutide 2.4 mg was associated with a greater body weight loss versus placebo; estimated treatment difference was –6.1 kg (95% CI, –7.2 to –5.0) [55] in STEP 2 (weight loss to week 68: semaglutide –9.7 kg vs placebo –3.5 kg). Weight loss in these clinical trials was sustained over 68 weeks. The most common AEs observed with semaglutide were gastrointestinal disorders (Table 3).

Table 3. Approved pharmacotherapies for obesity^*ठ[16]

Drug	Mechanism of action	Administration	Contraindication	Warnings	Common AEs
Phentermine (8 mg [short acting], 15 mg, 30 mg capsule, 37.5 mg tablet)	Sympathomimetic amine	15 mg or 37.5 mg orally once daily; 8 mg orally 2–3 times daily; can start with a quarter or half of a 37.5 mg tablet once daily and titrate upward to a maximum dosage of 37.5 mg	CVD, uncontrolled hypertension, agitated states, history of drug use, hyperthyroidism, glaucoma, or MAOI use within 14 days	Rare cases of primary pulmonary hypertension or serious regurgitant cardiac valvular disease	Increase in HR and/or BP, dizziness, dry mouth, constipation, insomnia and irritability
Orlistat (60 mg OTC, 120 mg)	Pancreatic and gastric lipase inhibitor	120 mg orally 3 times daily	Malabsorption syndrome or cholestasis	Malabsorption of fat-soluble vitamins A, D, E, and K	Flatulence, bloating, and diarrhea
Phentermine/topiramate ER^‖ (3.75/23 mg, 7.5/46 mg, 11.25/69 mg and 15/92 mg)	Combination of sympathomimetic amine, anorectic and ER antiepileptic drug	Start with 3.75/23 mg orally once daily for 14 days; increase to 7/46 mg once daily and monthly titration upward to achieve weight loss; discontinue if <3% weight loss on 11.25/69 mg or <5% weight loss on maximum dose of 15/92 mg after 12 weeks	Glaucoma, hyperthyroidism, or MAOI use within 14 days	Teratogenicity (risk of cleft palate and/or cleft lip), suicidal ideation, changes in memory or concentration, metabolic acidosis, hypokalemia (especially in patients on potassium-wasting diuretics), rise in creatinine levels, increase in HR, acute myopia, or acute angle-closure glaucoma	Peripheral neuropathy (usually transient), dyspepsia, insomnia, constipation, and dry mouth
Naltrexone SR (8 mg)/bupropion SR^‖ (90 mg)	Combination opioid antagonist and aminoketone antidepressant	Upward titration over 4 weeks to maximum of 2 tablets twice daily	Uncontrolled hypertension, seizure disorders, anorexia nervosa or bulimia, chronic opioid use, MAOI use within 14 days, abrupt discontinuation of alcohol or seizure medications	Suicidal ideation, decrease in seizure threshold, acute angle glaucoma, hepatotoxicity to naltrexone component and increase in HR and/or BP	Nausea, constipation, headache, vomiting, dizziness, dry mouth, and diarrhea
Liraglutide^‖ (3.0 mg)	GLP-1 receptor agonist	Start with 0.6 mg subcutaneously once daily for 7 days; titrate upward weekly to 1.2 mg, 1.8 mg, 2.4 mg, and then maximum dosage of 3.0 mg once daily	Family or personal history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN2) syndrome	Thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, increase in HR, renal impairment and hypoglycemia (with concomitant use of insulin secretagogue or insulin)	Nausea, hypoglycemia, diarrhea, constipation, vomiting, headache, decreased appetite, dyspepsia, abdominal pain, fatigue, dizziness, increase in lipase levels, and suicidal behavior or ideation
Semaglutide (2.4 mg)	GLP-1 receptor agonist	Start with 0.25 mg subcutaneously once weekly for 4 weeks; titrate upward in 4-week intervals until the maximum dose of 2.4 mg is reached	Personal or family history of medullary thyroid carcinoma or in patients with MEN2 syndrome	Thyroid C-cell tumors, acute pancreatitis, acute gallbladder disease, hypoglycemia (with concomitant use of insulin secretagogue or insulin), acute kidney injury, hypersensitivity, diabetic retinopathy complications	Nausea, diarrhea, vomiting, constipation, abdominal pain, headache, fatigue, dyspepsia, dizziness, abdominal distension, eructation, hypoglycemia in patients with T2D, flatulence, gastroenteritis, and gastroesophageal reflux disease
Setmelanotide (2 mg) For patients with obesity due to POMC, PCSK1, or LEPR deficiency	Melanocortin 4 receptor agonist	Patients ≥12 years of age: start with 2 mg (0.2 mL) subcutaneously once daily for 2 weeks; monitor patients for GI AEs and titrate dose accordingly	None	Disturbance in sexual arousal, depression and suicidal ideation, skin pigmentation and darkening of preexisting nevi, not approved for use in neonates or infants (due to benzyl alcohol preservative)	Injection site reactions, skin hyperpigmentation, nausea, headache, diarrhea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection

*Approved for BMI ≥30 kg/m² or ≥27 kg/m² with at least one comorbid condition such as diabetes mellitus, hypertension, hyperlipidemia or sleep apnea. ‡All contraindicated in pregnancy; medications should not be prescribed with known allergy or hypersensitivity to any drug components. §With co-use of antidiuretic medications, weight loss can cause hypoglycemia; serum glucose levels should be monitored before and during treatment. ^‖Effect on cardiovascular morbidity and mortality has not been established.

Pharmacotherapies for obesity management that are available in Europe, Asia, and/or Australia are sub-sets of those agents currently available in the United States.

5-HT_2c: 5-hydroxytryptamine receptor 2C, AE: adverse event, BMI: body mass index, BP: blood pressure, ER: extended release, GI: gastrointestinal, GLP-1, glucagon-like peptide-1: HR: heart rate, LEPR: leptin receptor, MAOI: monoamine oxidase inhibitor, MEN2: multiple endocrine neoplasia type 2, OTC: over the counter, PCSK1: proprotein convertase subtilisin/kexin type 1, POMC: pro-opiomelanocortin, SR: sustained release.

Historically, concerns regarding the long-term safety of anti-obesity agents have limited their use, especially for agents with significant adrenergic actions. When combined with lifestyle interventions, those who used prescription medications approved for long-term use lost 3% to 9% more of their starting body weight than those who did not take medication and received lifestyle interventions [56]. The risk-benefit of weight loss medications needs to be considered on an individual basis, but for many patients, the benefits outweigh the risks.

Anti-obesity agents that help delay the onset of T2D complications are vital tools in treating T2D, which is a common and serious comorbidity of obesity. Several clinical trials have evaluated the time to development of T2D as primary or secondary outcomes and demonstrated a role of these agents in diabetes prevention [57–59]. These include the Xenical in the prevention of diabetes in obese subjects (XENDOS) study, which evaluated orlistat as an adjunct to lifestyle changes for the prevention of T2D in patients with obesity. Orlistat plus lifestyle changes resulted in a greater reduction in the incidence of T2D over 4 years (HR, 0.63) and produced greater weight loss than lifestyle changes alone. However, the difference in T2D incidence was detectable only in those with impaired glucose tolerance [59]. A pooled analysis of 3 trials (CONQUER, EQUIP, and SEQUEL) assessing the efficacy and safety of phentermine-topiramate for weight loss in patients with obesity showed that there was a decrease in 1-year diabetes incidence rates in those treated with drug versus those receiving placebo [60]. The decrease was greatest in those at high cardiometabolic risk (placebo, 10.43% vs treatment, 6.29%), smaller in lower risk groups (intermediate, 4.67% vs 2.37%), and small in the low-risk category (1.51% vs 0.67%). The number needed to treat to prevent one new case of diabetes over a 56-week period was 24, 43, and 120 in those with high, intermediate, and low cardiometabolic risk, respectively [60]. A placebo-controlled trial in adults with prediabetes and overweight or obesity randomized participants to liraglutide 3.0 mg or matched placebo as an adjunct to diet and exercise. Liraglutide delayed the onset of diabetes by 2.7 times compared to placebo over a period of 160 weeks (95% CI 1.9–3.9, p <0.0001), corresponding to a hazard ratio of 0·21 (95% CI 0.13–0.34) [61]. Liraglutide also induced a greater weight loss than placebo (treatment difference to week 160: –4.6 kg [95% CI, –5.3 to –3.9]; liraglutide –6.5 kg vs placebo –2.0 kg; p <0.0001). Data from several clinical trials have also demonstrated that anti-obesity medications can delay the onset of T2D-associated complications by optimizing glucose, blood pressure, and lipid control (Figure 2) [62].

Figure 2. Anti-obesity medications and T2D risk management [62]. Data from XENDOS trial (orlistat) = 4-year duration; CONQUER trial (phentermine-topiramate), COR-1 trial (naltrexone/bupropion), and SCALE trial (liraglutide) = 56-week duration. ER: extended release, FPG: fasting plasma glucose, PP2: postprandial 2-hour plasma glucose, SBP: systolic blood pressure, SR: sustained release, T2D: type 2 diabetes, TC: total cholesterol, TG: triglyceride.

From Oh TJ. The role of anti-obesity medication in prevention of diabetes and Its complications. J Obes Metab Syndr. 2019;28:158–166, licensed under CC BY-NC 4.0.

5.4. Surgical options

Bariatric surgery (Table 4) [63–67] can produce marked and sustained weight loss that is not achievable with other methods. Interestingly, the most recent pharmacotherapeutic approaches mimic the effects of bariatric surgery. As mentioned earlier, weight loss associated with RYGB surgery alters the epigenome in adipose tissue, skeletal muscle, and blood.

Table 4. Surgical options [63–67] (Arterburn AIM 2018; Topart 2017; Marinari 2006; Cottam 2020)

Bariatric procedure	Advantages	Disadvantages	Total body weight loss at year 1 [64]	Total body weight loss at year 5 [64]
Vertical sleeve gastrectomy (VSG)	Improves metabolic disease Maintains small intestinal anatomy Micronutrient deficiencies infrequent Most common bariatric surgical procedure Can be part of a staged approach	Gastroesophageal reflux disease Limited long-term data	25%	19%
Roux-en-Y gastric bypass (RYGB)	Greater improvement in metabolic disease Large dataset available	Increased risk of malabsorptive complications over VSG Technically more challenging than LAGB or VSG	31%	26%
Laparoscopic adjustable gastric banding (LAGB)	Least invasive Removable	5-year removal rate (international) 25% to 40% Any metabolic benefits are dependent on weight loss	14%	12%
Biliopancreatic diversion with duodenal switch (BPD-DS)	Greatest amount of weight loss, and resolution of metabolic disease	Greater risk of macro- and micronutrient deficiencies versus RYGB Technically challenging	41% [65]	37% [66]
Loop duodenal switch	May be simpler and safer than BPD-DS, with fewer micronutrient deficiencies	Long-term data not available Two-step procedure	37% [67]	(Limited data available)

The current AACE guidelines recommend bariatric surgery for patients with a BMI ≥40 kg/m² without coexisting medical conditions, or a BMI ≥35 kg/m² and ≥1 severe obesity-associated comorbidity (e.g. T2D, NAFLD, nonalcoholic steatohepatitis [NASH]), or a BMI 30.0–34.9 kg/m² with T2D or metabolic syndrome [40]. The ADA has similar recommendations, but includes separate BMI cutoffs for Asian American patients (BMI ≥40 kg/m² [≥37.5 kg/m² in Asian Americans] or BMI 35.0–39.9 kg/m² [32.5–37.4 kg/m² in Asian Americans], and BMI 30.0–34.9 kg/m² [27.5–32.4 kg/m² in Asian Americans] with T2D or metabolic syndrome) [43].

Common bariatric surgeries include sleeve gastrectomy and gastric bypass (RYGB) (Table 4) [63–67]. These procedures result in weight loss beyond what would be expected from caloric restriction and malabsorption and are associated with reduced appetite and increased satiety. This is in contrast to what is observed during dietary weight loss, which is frequently associated with increased hunger and decreased satiety (Figure 3) [68]. The mechanism underlying this effect is thought to be linked to altering the body weight set point to a lower weight, thus supporting more sustained weight loss. Additionally, it has been shown that bariatric surgery improves long-term mortality [69,70], and can lead to remission of several comorbidities, including T2D [71–74].

Figure 3. Diet versus RYGB surgery [68]. GLP-1: glucagon-like peptide-1, PYY: peptide YY, RYGB: Roux-en-Y gastric bypass.

From Pucci A, Batterham RL. Mechanisms underlying the weight loss effects of RYGB and SG: similar, yet different. J Endocrinol Invest. 2019;42:117–128, licensed under Creative Commons CC BY.

The Longitudinal Assessment of Bariatric Surgery (LABS) study demonstrated that RYGB surgery was associated with T2D remission in patients with obesity and T2D, which was sustained for up to 7 years [71,72]. The STAMPEDE study assessed 5-year outcomes in 150 patients with T2D and a BMI of 27–43 kg/m², and demonstrated that intensive medical therapy plus RYGB or sleeve gastrectomy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia [73]. Finally, laparoscopic adjustable gastric banding produces the least significant and sustained weight loss of the bariatric surgeries [75]. Thus, bariatric surgery can be an appropriate treatment option for some patients, and some procedures can also treat certain comorbidities, such as T2D. Pharmacotherapy can also be used to prevent and treat post-bariatric surgery weight gain and improve outcomes.

Endoscopic techniques represent newer approaches to weight management that can be used independently or in concert with traditional medical and surgical treatments for obesity [8]. These less invasive procedures may increase the appeal across a broader patient population and include the Maestro neuroregulator, the REShape integrated dual balloon system, the Obalon balloon, the AspireAssist system, the transpyloric shuttle, as well as Plenity hydrogel capsules, the only orally administered option.

6. Maintenance of weight loss

Long-term maintenance of weight loss is one of the primary challenges for patients and HCPs alike. Based on data from the Centers for Disease Control and Prevention (CDC) from 2013 to 2016, approximately half of adults in the United States have tried to lose weight [76]. Studies have shown that only about 20% of patients are successful in maintaining their weight loss long term with lifestyle interventions [77]. A meta-analysis of 29 long-term weight loss studies showed that >50% of weight lost was regained after 2 years, and 80% was regained by 5 years [78]. Another study examined weight data in >14,000 participants from the 1999–2006 NHANES. Among those who ever had overweight or obesity, 37% and 17% maintained 5% and 10% weight loss, respectively, for 1 year [79]. Over this relatively short time period, ~60% and ~20% of patients regained the weight lost.

7. Patient-HCP communication [80]

In order to aid HCPs in addressing obesity issues with their patients, the use of the 5 As model, adapted for obesity, can be useful.

Ask – Ideally, initial questions should seek the patient’s permission to talk about weight, because it is a sensitive issue. Avoid using judgmental language and do not make assumptions about the patient’s lifestyle.

Assess – A comprehensive assessment of the patient’s health status as it relates to obesity and associated comorbidities is necessary. This includes BMI and waist circumference, but BMI alone should never serve as the sole indicator of intervention, comorbidities (e.g. T2D, hypertension, dyslipidemia, depression), effects of medications on body weight, sleep pattern, stress levels, mental health status, diet and exercise habits.

Advise – Use the information obtained from assessing the patient’s situation to advise them on potential strategies for weight loss. Ask permission to give advice on weight, and emphasize that it is not their fault, and not due to a lack of willpower. Educate patients about obesity as a chronic condition that will require a long-term effort. Manage expectations about expected weight loss (5%–10%) and emphasize that even moderate weight loss will improve concomitant conditions. An important aspect of the assessment is a review of a patient’s chronic medications to determine whether any of these agents contribute to weight gain. If possible, weight-promoting agents should be exchanged for any that are weight neutral or promote weight loss. Obesity guidelines provide information on who is a candidate for intervention; for example, patients with a BMI >27 kg/m² with presence of comorbidity or a BMI >30 kg/m² should receive treatment. Although lifestyle changes continue to be cornerstones of initial obesity treatment, a lack of response without clinically meaningful weight loss (3%–5%) requires prompt escalation of therapy. There are many FDA-approved anti-obesity medications available and pharmacotherapy should be initiated promptly when patients meet the criteria. The Endocrine Society Clinical Practice guidelines suggest prescribing at least one weight loss-promoting agent (e.g. metformin, sodium glucose co-transporter 2 [SGLT2] inhibitor, GLP-1 receptor agonist, pramlintide) to those with obesity and T2D requiring insulin [17]. Patients with concomitant hypertension should receive angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Those with concomitant depression should receive a selective serotonin reuptake inhibitor (SSRI), such as fluoxetine or sertraline, or bupropion. In patients who have severe obesity, bariatric surgery should be considered because of the effects on gut hormones, appetite suppression, increased satiety, and improved glucose metabolism.

Agree – Realistic weight loss targets and behavioral changes should be negotiated and agreed upon, securing the patient’s buy-in to the proposed plan.

Assist – It is important to identify a patient’s barriers to weight management (whether they are social, medical, economical, or emotional) and provide resources to address these barriers, including diabetes self-management education for those with T2D, referrals to specialists, or help with insurance claims.

8. Conclusions

The treatment of obesity remains challenging for HCPs and requires an understanding of energy homeostasis, which is a more complex process than passive accumulation of excess calories and involves both central and peripheral pathways and their complex interplay. Steady-state body weight is determined by different factors that include genetic, hormonal, environmental, and behavioral components. The recognition of obesity as a chronic disease is an important step in developing individualized treatment plans that consider obesity-associated comorbidities, such as type 2 diabetes. Although lifestyle changes are still central to a personalized approach, pharmacotherapy and bariatric surgery need to be considered for eligible patients, especially those with obesity-associated comorbidities.

9. Expert opinion

The critical realization that obesity is a chronic disease with devastating health consequences requiring long-term treatment approaches is changing the way we think about the condition. HCPs are beginning to recognize that telling their patients to eat less and exercise more does not lead to sustained weight loss. The underlying pathophysiologic mechanisms of obesity are multifactorial and need to be addressed accordingly to reduce the significant morbidity and mortality. The hypothalamus plays a pivotal role in the energy homeostasis, integrating central signals from the orexigenic AgRP/NPY neurons and the anorexigenic POMC neurons, 2 opposing systems that regulate appetite, food intake, and energy expenditure. The hypothalamus also integrates signals from hedonic pathways in the corticolimbic system, which are associated with food palatability. These pathways can override the homeostatic system, increasing the drive to eat palatable foods despite physiologic satiety. Finally, the hypothalamus integrates peripheral signals from the GI tract, pancreas, adipose tissue, liver, and muscle that provide information on nutrient status and energy stores. These signals include anorexigenic gut hormones such as GLP-1, PYY, and CCK, which are secreted in response to food intake and promote satiety; and ghrelin, produced in the stomach, the only known orexigenic hormone, which stimulates appetite and promotes eating.

With the obesity epidemic and its noted relationship to outcomes during the COVID-19 pandemic, all HCPs are called upon to assess and advise their patients with obesity more effectively. Lifestyle interventions, such as appropriate nutrition, physical activity, and behavioral therapy remain the cornerstones of obesity treatment. However, these measures alone are rarely adequate in those with obesity, as long-term weight loss/maintenance remains elusive due to the chronic nature of the disease and the body’s counter-regulatory response to weight loss. Moreover, lifestyle interventions do not significantly reduce much of the obesity-associated morbidity or mortality. From an evolutionary standpoint our bodies are designed to maintain body weight in times of low food supply; this is accomplished with the complex interplay of pathways contributing to energy homeostasis. As people lose weight, their bodies produce more hormones that induce hunger, and fewer anorexigenic hormones that suppress it. In other words, diet-induced weight loss triggers biological adaptations that favor weight regain, such as increased appetite, reduced satiety signals, and altered food preferences and cravings. Therefore, appropriate interventions, such as pharmacotherapy or bariatric surgery are indicated for many patients and should be recommended in cases of insufficient weight loss or weight regain. Advice for treatment considerations should include assessment of comorbidities or risk factors, as many anti-obesity agents and bariatric surgeries have beneficial effects on other weight-associated comorbidities, including type 2 diabetes. Most approved weight loss agents act centrally by targeting appetite and promoting satiety, and also may have effects on cravings and energy expenditure. Combining pharmacotherapy with lifestyle changes increases a person’s chance of losing weight and maintaining that loss. Bariatric surgery is considered the gold standard for people with very high BMIs. These procedures result in weight loss beyond what would be expected from caloric restriction and, in contrast to dietary weight loss that often results in increased hunger and decreased satiety, are associated with reduced appetite and increased satiety. Here as well, combining bariatric surgery with lifestyle changes and pharmacotherapy will provide the best chance for continued success. Medical devices such as the Plenity hydrogel capsules and intragastric balloons are additional tools that are now available. These devices are becoming increasingly popular, generally produce weight loss in a range between medications and bariatric surgery, and also play a role in the management of obesity for appropriate patients. HCPs need to be aware of the neurohormonal pathways that influence appetite, satiety, and weight regulation, and the anticipated efficacy of treatment options so they can make the most appropriate treatment recommendations for their patients. Medications or other treatment modalities that may contribute to obesity should be avoided, and other interventions that can improve metabolic regulation (e.g. sleep hygiene, stress management) should be advised. Obesity is a complex, chronic disease with significant health impacts, but it can be positively influenced with appropriate assessment, treatment, and management. Our understanding of obesity has expanded, and the coming years will move this area forward with new, more effective treatment options and an increased focus on managing obesity-associated comorbidities.

Article highlights

• Obesity is a chronic disease with serious health consequences.

• Its underlying pathophysiology is a dysregulation of the body’s energy balance system, which is controlled by a complex interplay of neural, hormonal, and metabolic pathways.

• Lifestyle interventions remain the cornerstones of treatment; however, these measures alone are rarely enough for the long-term management of obesity.

• Appropriate interventions, such as pharmacotherapy or bariatric surgery, are indicated for many patients and should be recommended.

• Treatment considerations should include assessment of comorbidities or risk factors, as many anti-obesity agents and bariatric surgeries also have beneficial effects on weight-associated comorbidities.

Financial and competing interests disclosure

RB Kumar is a speaker for Novo Nordisk and Janssen Pharmaceuticals, a consultant to Gelesis; and reports holding shares of Vivus, Myos Corp, and Zafgen. LJ Aronne reports receiving consulting fees from and/or serving on advisory boards for Jamieson Laboratories, Pfizer, Novo Nordisk, Eisai, Real Appeal, Janssen, and Gelesis; receiving research funding from Aspire Bariatrics, Allurion, Eisai, AstraZeneca, Gelesis, Janssen, and Novo Nordisk; having equity interests in BMIQ, ERX, Zafgen, Gelesis, MYOS, and Jamieson Laboratories; and serving on a board of directors for BMIQ, MYOS, and Jamieson Laboratories. G Srivastava reports advisory fees from RHYTHM and Novo Nordisk. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Writing support was provided by Linda Merkel, PhD, of Elevate Medical Affairs, Envision Pharma Group Ltd, which was contracted and compensated by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) for this service. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Additional information

Funding

Writing support for this manuscript (provided by Elevate Medical Affairs, Envision Pharma Group Ltd) was contracted and compensated by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI).