The obesity epidemic: molecular and clinical considerations

Obesity is considered to be an epidemic of the 21st century; >2 billion individuals are considered to be overweight or obese globally. In this Primer, Martinez and colleagues discuss obesity and its association with pathophysiological abnormalities that increase health risk, such as features of the metabolic syndrome.

Adipose tissue inflammation is an adaptive response to overnutrition in the early stages of obesity, but later becomes maladaptive. Here, Reilly and Saltiel review the cellular and molecular mechanisms of obesity-induced inflammation in adipose tissue and discuss potential therapeutic approaches.

Combating the obesity epidemic necessitates a range of effective therapies. In this Review, Dixon and Lee explore the medical devices developed to bridge the gap between conservative lifestyle and pharmacotherapy interventions and disruptive surgical approaches, focusing on mechanisms of action, efficacy and safety.

Obesity is a risk factor for the development of cardiovascular diseases. In their Review, Lavie and colleagues summarize the deleterious consequences of obesity in patients with cardiovascular disease, review the available data on the benefits of weight loss, and explain the 'obesity paradox' phenomenon in this setting.

The cardiovascular benefits of weight loss in patients with obesity are well documented. Bariatric surgery is an effective and long-lasting strategy for weight loss, and can improve many cardiovascular risk factors such as hypertension and dyslipidaemia. In this Review, Beamish and colleagues highlight the effects of bariatric surgery on cardiovascular risk factors and outcomes.

Recent large-scale genome-wide association studies have identified numerous variants that are associated with obesity-relevant traits such as body mass index or body fat percentage. Here, the authors explore to what extent this genomic evidence matches the evidence from functional and mechanistic studies.

As not all individuals with obesity respond to lifestyle modification, pharmacotherapy has a key role in tackling the obesity epidemic. Here, Gitanjali Srivastava and Caroline Apovian review the six currently available FDA-approved anti-obesity drugs in terms of safety, efficacy and clinical utility.

Dyslipidaemia is a major contributor to the onset of metabolic disease. Here, Meikle and Summers discuss lipidomic research into relationships between diet, lipid metabolism and metabolic disease. The Review also highlights promising potential therapeutics that target lipid metabolism to counteract obesity, insulin resistance and type 2 diabetes mellitus.

In obesity, individuals develop resistance to leptin and ghrelin, which have important functions in the neuroendocrine control of energy homeostasis. Here, Cui and colleagues discuss the mechanisms that lead to leptin and ghrelin resistance, and how they might be exploited as targets for the management and treatment of obesity.

The incidence of obesity-related glomerulopathy (ORG) — a distinct entity featuring proteinuria, glomerulomegaly, progressive glomerulosclerosis and renal functional decline — is increasing in parallel with the obesity epidemic. Here, Vivette D'Agati and colleagues review the pathology, clinical features, treatment and pathogenesis of ORG.

Brown adipocytes (which reside in brown adipose tissue) and beige adipocytes (which develop in white adipose tissue in response to cold) expend energy to produce heat and are therefore important in regulating body temperature and body weight. Recent studies provide insights into the developmental origins of brown and beige adipocytes and into the regulation of their differentiation and function.

In this Review, Lício Velloso and colleagues describe the main components involved in the proteostasis network and consider how defects in these components might interfere with the correct function of the hypothalamus in obesity and ageing.

New approaches are required for the prevention and treatment of obesity and its associated pathologies. Here, Martel and colleagues review the potential anti-obesogenic and antidiabetic effects of plants, mushrooms and their derivatives, some of which have longstanding uses in traditional Chinese medicine.

Peroxisome proliferator-activated receptors (PPARs) are integrators of both inflammatory and metabolic signalling networks. In this Review, the authors provide a comprehensive overview of how PPARs contribute to the development of metabolic disorders and how pharmacologically targeting these pathways can be used to develop new therapeutics for such diseases.

Obesity affects 15–40% of patients with IBD. Here, Singh and colleagues discuss the evidence linking obesity to IBD pathogenesis, the effect of obesity on disease outcomes and treatment response, and obesity-related issues in abdominal imaging and IBD surgery.

Obesity is a major public health problem worldwide, and bariatric surgery offers an effective option for treatment of obesity and related comorbidities. Here, Nguyen and Varela discuss the indications, safety and outcomes of different bariatric operations in obesity and related metabolic disorders, such as type 2 diabetes mellitus, and examine emerging surgical treatment options.

Research over the past few decades has elucidated the biochemical mechanisms underlying insulin receptor signalling. Recent insights into the complexity of its temporal and tissue-specific regulation, which involves various combinations of signalling modules in different cell types, are shedding light on the pleiotropic effects of insulin action and the pathogenesis of insulin resistance.

The concept of food addiction as an explanation for the rise in obesity has become increasingly popular. In this Opinion article, Graham Finlayson critically evaluates the food addiction hypothesis and highlights several problems with its use.

The discovery of the receptors for the protein GDF15 suggests that it regulates food uptake through the emergency pathway — a neuronal circuit that causes weight loss in response to cancer, tissue damage and stress. See Letter p.255

Here, five leading researchers describe changes in the epidemiology of obesity-related kidney disease, advances in current understanding of the mechanisms involved and current approaches to the management of affected patients.

Whether obesity is a cause of type 2 diabetes mellitus and coronary heart disease or a shared risk factor has been an enduring subject of debate. Lyall and colleagues have used Mendelian randomization to conclude that there is a causal relationship between obesity and cardiometabolic disease. However, the analyses fail key inherent assumptions. The article does not negate a large body of data indicating that insulin resistance is the primary mechanism driving the progression of cardiometabolic disease.

NAFLD, the hepatic manifestation of the metabolic syndrome, is a multifactorial condition — environmental factors influence an inherited genetic risk. Stender et al. now describe the additive effect of obesity and NAFLD-associated genetic polymorphisms on steatosis, elevated serum alanine aminotransferase levels and cirrhosis, remarkably illustrating the principle of gene–environment interactions.

The infrapatellar fat pad and other adipose tissues in close proximity to the joint have been linked with osteoarthritis (OA), but the nature of this relationship is unclear. Two new studies elucidate the features of intra-articular adipose tissues in OA and raise important questions for future investigations.

A novel image-analysis method using standard CT imaging demonstrates that changes in the CT signal of coronary perivascular adipose tissue are associated with the degree of inflammation in adjacent coronary plaques. This exciting development might become a useful adjuvant clinical tool, although further validation and prospective outcome studies are required.

A new population-based observational cohort study involving more than 1.2 million live births highlights the increased risk of congenital anomalies with increasing degrees of maternal overweight and obesity. However, by only considering data on live-born infants, the full impact of maternal overweight and obesity on this aspect of reproductive and child health is underestimated.

A distinct subset of natural killer cells with a myeloid signature is associated with metainflammation.

Many students experience weight gain during their first year of college, which has been attributed to environmental changes, including eating habits and activity patterns. A new study implicates the endogenous metabolite and sugar substitute, erythritol, as a novel physiological marker predictive of vulnerability to increased adiposity.