Recent Advances in Obesity Research

The increasing prevalence of childhood obesity, as well as the recognition of the role of early factors for the development of cardiovascular disease, called the attention to the impact of the dynamics of adiposity across pediatric age on adult health outcomes, highlighting the potential application of life course frameworks in this context. Therefore, there is increasing interest in identifying critical and sensitive periods for obesity development and to identify how to summarize lifetime exposure to adiposity/obesity to measure its impact on cardiovascular disease. The discussion of the application of the life course approach to the study of obesity determinants and its relation with cardiometabolic health is presented in this chapter. Additionally, different methods to summarize the cumulative exposure to adiposity are described as well as the challenges of measuring direct and indirect effects of childhood adiposity on adult cardiovascular disease.

The understanding of obesity’s etiology has broadened from an individual to a more comprehensive perspective of environmental influences, based in social ecological models. Interventions to tackle obesity are dependent on understanding interactions within complex systems and on changing modifiable risk factors with high impact at the population level. In this chapter, literature on social and behavioral factors associated with obesity was reviewed. Socioeconomic factors seem to be main drivers of obesity. This effect may act indirectly through mediators such as diet and physical activity. The transgenerational profile of both socioeconomic conditions and obesity should also be highlighted. Thus, these influences should be taken from a lifecourse perspective. The establishment of obesity is nested in early life and the family context, including feeding practices, parents’ dietary habits and lifestyles, and parental obesity, are proximal determinants of childhood obesity. Pregnancy, breastfeeding and weaning are identified as sensitive periods for establishing eating habits and therefore obesity development. Research has focused extensively on the effects of diet and physical activity on the energy balance; however, there seems to exist a lack of consistent associations. Evidence is more robust regarding the protective effects of vegetables, whole grains and the Mediterranean Diet, and the detrimental effect of sugar-sweetened beverages and sedentary behaviors, namely television viewing, particularly in children. Smoking and moderate alcohol drinking have been negatively associated with obesity, but a confounding effect of a general lifestyle profile cannot be excluded. The influence of smoking during pregnancy on later childhood obesity is supported by more robust evidence.

Adipose Tissue (AT) is an endocrine organ with a key role in the regulation of the energy homeostasis. White AT accumulates energy in the form of triglycerides within lipid droplets and, therefore, is particularly abundant in obesity. In contrast, brown AT is specialized for energy expenditure playing a pivotal role on thermogenesis control and its mass decreases with obesity. AT secretes a large number of adipokines that regulate the central control of appetite and the metabolism of diverse peripheral tissues. This secretion and also the anatomical features of AT are closely related with the nutritional status and, naturally, strongly differ between normal weight and obese individuals. AT remodeling is indeed an ongoing process, that is pathologically exacerbated in the obese state. This review will discuss and present updated data describing the main changes in AT that correlate with an obese status. In obesity, AT changes in mass, capacity for energy storage, distribution through the organism, cellular composition, endocrine role and signaling. In summary, the chronic excess of nutrient supply leads to adipocyte hyperplasia and hypertrophy, hypoxia, mitochondrial dysfunction, proinflammatory signaling, adipokine secretion and, ultimately, to cell death. The extent of AT remodeling is closely associated with the pathophysiological consequences of obesity, including insulin resistance, cardiovascular disease, hypertension and hepatic steatosis.

The recognition that certain obese patients do not exhibit unfavorable metabolic changes, with a low risk for cardiovascular disorders, and that some individuals with a normal weight develop metabolic complications such as insulin resistance, gave rise to the idea that in obesity not only adipose tissue (AT) quantity matters but also AT function, with more relevance. It is known, that impaired AT function is caused by the interaction of genetic and environmental factors which lead to adipocyte hypertrophy, hypoxia and a variety of stresses, including inflammatory processes within the AT. Indeed, AT dysfunction translates into the imbalance between pro- and anti-inflammatory adipokines produced in the adipocyte and secreted into the systemic circulation. For instance, AT dysfunction has been characterized by decreased release of homeostatic protective factors (such as adiponectin, omentin or vaspin) and increased activation of stress-related pathways leading to pathological adipokine (leptin, resistin and visfatin) formation. Systemically, AT dysfunction promotes metabolic and vascular alterations, namely low-grade inflammation, hypercoagulability, hypertension, dyslipidemia and insulin resistance. Thus, diagnosing AT dysfunction is of clinical relevance, serving as a tool for stratifying risk for cardiovascular disease or type 2 diabetes mellitus, and may guide preventive treatment with both medication and lifestyle interventions. It is believed that in the near future, a set of pro- and anti-inflammatory adipokines could be compiled, providing clinicians with an 'adipokine-score' indicative of the level of AT dysfunction. In this chapter, we briefly discuss the current knowledge about the emerging biomarkers of dysfunctional AT and their potential impact on metabolic diseases associated with obesity.

The idea that there is heterogeneity among obese individuals in their risk for disease is not new, and may have begun with the acknowledgement that the distinct cardiovascular disease risk between males and females was influenced by their body pattern of adipose tissue accumulation (i.e. predominantly in the upper body versus in the lower body, respectively). Later came the debate on the pathophysiological meaning of adipose tissue accumulation in visceral as opposed to subcutaneous depots and even of distinct patterns of adipose tissue growth (hyperplasia versus hypertrophy). More recently, epidemiological evidence has shown that individuals with similar degrees of obesity may be at different ranges of metabolic abnormality and cardiometabolic risk spectrum. In addition, many subjects not fulfilling the criteria for obesity diagnosis share the same metabolic disturbances of some obese individuals. Although, it has been discussed that healthy obese people will sooner or later become unhealthy, the question on why some subjects attain a status of metabolic chaos earlier than others (for the same obesity levels or adipose tissue amount) is still matter of debate. In this chapter, we propose to discuss the contribution of obesity-related inflammation – metabolic inflammation – as cause or consequence of different obesity phenotypes, overviewing the main possible adipose tissue inflammation triggers.

Understanding the myriad of factors contributing to obesity is essential for curbing its decade-long expansion. Recently, despite the evidence of traditional contributing factors, the role of environmental chemicals with endocrine disrupting activity has also been highlighted. Undeniably, even very small concentrations of these endocrine disrupting chemicals (EDCs) have the capacity to induce severe health damages. The “environmental obesogen” hypothesis associates EDCs to the disruption of energy homeostasis, in particular because of their ability to modulate adipocyte biology. Further studies have revealed numerous potential mechanisms, including modulation of nuclear hormone receptor function and modification of the epigenome. More recently, their involvement in exacerbating metabolic dysfunction in an obesity context reinforces the hypothesis that EDCs have an important “environmental dysmetabolic” effect. Besides adulthood exposure, the perinatal effects are very important since they may allow a change in metabolic programming, encouraging the further development of obesity. Consequently, additional research directed at understanding the nature and action of EDCs will illuminate the connection between health and environment as well as the possible effects triggered by these compounds in respect to public health. Nutrition is being further substantiated as an important modulator of inflammatory and antioxidant pathways, especially associated with environmental insult; nutrition is also emerging as a tool to address exposure toxicity of ECDs as both a sensing and remediation platform. Ultimately, improving EDC exposure measurement, reducing confounding bias, identifying discrete periods of vulnerability and quantifying the effects of EDC mixtures will enhance inferences originated from epidemiological studies.

Obesity is a common, chronic, complex, and multifactorial disorder and its management requires a multidisciplinary approach, including diet, exercise, behavior modifications, and drugs, all of which are key components of the treatment. Antiobesity drugs often have to be prescribed, despite adherence to appropriate lifestyle modifications. The goal of pharmacological management of obesity is not only to induce weight loss, but also to improve comorbidities associated with obesity, namely the components of metabolic syndrome, sleep apnoea, etc., and also to help patients maintain compliance, maintain body weight loss, prevent weight regain, as well as to improve their quality of life. The efficacy of the treatment should be evaluated after the first three months, and the drug should be withdrawal in nonresponders, or - if possible - an alternative therapy may be tried. There are marked differences regarding drug availability in the world, however the long-term use of approved antiobesity drugs is limited to five drugs (orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, and liraglutide), all of which must be used in conjunction with lifestyle intervention. We will review currently approved antiobesity medications, focussing mainly on clinical aspects, and we will also discuss some of the new drugs that are in the pipeline.

The recognition of obesity as a chronic disease and its relentless expansion throughout the world in the last few decades has driven the need for more efficient treatments. Pharmacological approaches have been attempted since the twentieth century, but most of the drugs failed to demonstrate an adequate balance between weight loss and side effects. In the last few years, new, less stringent criteria from the Food and Drug Administration allowed the introduction of new compounds or combinations of old ones. The single new compounds are lorcaserin, an agonist of central 5HT2C receptors and liraglutide, an agonist of glucagon-like peptide 1 receptors. New, fixed-dose combination drugs are naltrexone-bupropion (an opioid antagonist and an antidepressant, respectively) and phentermine-topiramate (a central noradrenaline release stimulant and an antiepileptic, respectively). Orlistat, an inhibitor of gastrointestinal lipases, has also been available for some years. Weight loss effect after one year found in double blind, placebo controlled clinical trials ranges from circa 3 kg for orlistat and lorcaserin to 9 kg for the phentermine-topiramate combination. Drugs with higher weight reductions generally present a higher probability of adverse effects. The relatively modest effect of all the drugs approved for obesity treatment clearly shows that pharmacotherapy cannot be the sole solution for the overwhelming obesity epidemic. Nevertheless, a more personalized use of the existing compounds and the possibility of new drugs based on different mechanisms may certainly help to circumvent the powerful energy-conserving mechanisms that make sustained weight loss extremely difficult to achieve.

Obesity is associated with several comorbidities, especially cardiovascular and metabolic diseases. Bariatric surgery is the most effective treatment for obesity, leading to long-term weight loss, reversal of the associated diseases and reduction in long-term mortality. The relative effectiveness of each type of surgery is not yet fully clear, but all the surgeries lead to a significant improvement in metabolic diseases. Resistance to insulin is associated to obesity and is an essential step in the pathophysiology of diabetes. The metabolic effects of surgery (most studied are the effects of gastric bypass) lead to an early improvement of insulin resistance even before significant weight loss has occurred. Metabolic syndrome clusters several cardiovascular risk factors and is increased in obese patients. Surgery leads to remission of metabolic syndrome in up to 80% of patients. The remission of type 2 diabetes after surgery is significantly greater after surgery than with the best medical management, varying between 50-80%. Severity and control of type 2 diabetes are related to the resolution rates after surgery. Coronary artery disease, atherosclerosis, gastro-esophageal reflux disease, obstructive sleep apnea, cardiac failure, renal failure, non-alcoholic hepatic steatosis and other obesity-associated diseases are significantly improved after bariatric surgery. Patients with higher body mass indexes and lower disease burden seem to be those that improve the most, achieving higher remission rates of obesity-associated diseases. Even in the most severe forms of uncontrolled metabolic disease, bariatric surgery leads to a significant improvement of comorbidities.

Obesity has reached epidemic proportions in the last decades and as so successful weight loss diets have been pursuit. Different dietary approaches, with distinct macronutrients distribution, have been studied. Low-fat, low-carbohydrate and/or high-protein diets are among the most used diets for obesity research and in clinical practice. However, their effects on obesity management, including in metabolic complications often associated, are not completely clarified. Moreover, additional questions arose inside each macronutrient group, being the following ones just a few: are all sugars equal for weight control? How does saturated vs. unsaturated fatty acids ingestion affect weight loss? What are the differences between animal or vegetable protein intake, regarding weight management? Taking all evidence together, it seems impossible to define an ideal macronutrients’ distribution for weight loss and maintenance that fits everyone. Energy-restricted diets continue to be the most successful weight loss strategy, independently of macronutrient distribution. However, severe restriction of fat or carbohydrates do not seem to have an additional benefit for weight control as compared to a more balanced macronutrient distribution, as occurs in Mediterranean diet. Importantly, diets must be individualized and based on the personal and cultural preferences in order to promote a successful weight loss and maintenance in the long-term.

Polyphenols are secondary metabolites from plant metabolism, widely distributed in nature. The major dietary sources of polyphenols are fruits, vegetables, chocolate and plant-derived beverages like tea, coffee and wine. Polyphenols are mostly absorbed in the small intestine, extensively and quickly metabolized in the liver and appear in the circulation or are excreted into bile and urine as both intact and metabolized forms. Much attention has been given to polyphenols in the last decades, mainly due to the positive association between the consumption of polyphenol-rich foods and the low risk of chronic diseases like cardiovascular diseases, type 2 diabetes and obesity. In fact, obesity has increased enormously worldwide and is becoming a threat to public health. Several studies suggest that polyphenols and polyphenol-rich foods have very interesting properties regarding the management of obesity and weight loss. Polyphenols promote a healthy profile of intestinal microbiota, decreasing Firmicutes and increasing Bacteroidetes. Polyphenols may modulate carbohydrate digestion, glucose absorption and gluconeogenesis, thereby helping contain postprandial hyperglycemic excursions. They improve lipid metabolism by decreasing adipogenesis and inhibiting lipogenesis, and stimulating lipolysis and beta-oxidation. Polyphenol ingestion was also associated with decreased food-intake and thermogenesis stimulation. Nevertheless, the effects described are still subject to debate because human studies are scarce and some results are inconsistent. Further research is needed before recommending the use of polyphenols as regulators of weight and/or modulators of obesity.

The rapid increase in the incidence and prevalence of obesity and metabolic syndrome over the last decades cannot be explained solely by genetic and adult lifestyle factors. There is now considerable evidence that the fetal environment also strongly influences the risk of developing such diseases in later life. One of the principal environmental factors influencing the developing child is nutrient availability, which is dependent on maternal nourishment status and placental functionality. The influence of a nutritional insult to the fetus will not only depend on the type of maternal nutritional insult but will also depend on the maternal metabolic condition, the timing of maternal nutritional insult, and will occur when there is a mismatch between pregnancy and postnatal environments. Both human and animal studies have shown that maternal under- (caloric restriction, protein restriction or micronutrient restriction) or overnutrition (high-fat, high-carbohydrate or high-vitamin diets) can induce persistent changes in gene expression and metabolism in the offspring, resulting in an increased risk for obesity and metabolic disease. Because these changes are mediated by altered epigenetic regulation of specific genes, and given that epigenetic marks are reversible, nutritional or pharmaceutical interventions may be used to modify long-term obesity and cardio-metabolic disease risk.

Despite the multifactorial etiology of obesity, the attention of the scientific community is now focused on the collection of microorganisms that inhabit the human gut (the gut microbiota) and on their effects upon energy harvest and metabolic signaling. The gut microbiota is involved in the pathophysiology of obesity and several mechanisms are behind this association, e.g. increased capacity to extract energy from undigested components of the diet, regulation of fat storage and fatty acid oxidation, bile acids transformation, endocannabinoid system modulation and metabolic endotoxemia. In this chapter, different therapeutic approaches (prebiotics, probiotics and fecal microbiota transplants) designed to modulate the gut microbiota composition towards better results and success rates in obesity management are reviewed and summarized. In conclusion, the gut microbiota might represent a useful marker for determining susceptibility to metabolic disease, as obesity, and be useful in disease diagnosis and monitoring of disease progression.

Regular physical exercise (PE) has been recognized as one of the most powerful lifestyle strategies used to mitigate overweight and obesity. In this context, white adipose tissue (WAT) plays a pivotal role as it is the largest site of storage and release of excess energy, thus participating in important metabolic, endocrine and inflammatory functions, which are intricately linked to the etiology and pathophysiology of obesity-associated chronic diseases. Moreover, current literature reports that PE, besides reducing visceral fat accumulation, also mitigates obesityinduced dysregulated adipokine synthesis and release, resulting in systemic metabolic improvements through beneficial dynamics changes in WAT. More recently, PEinduced hormone secretion by skeletal muscle has been described as a potential mechanism for inducing a brown fat-like phenotype in WAT. Thus, the modulatory impact of PE on WAT may also occur through the cross-talk between skeletal muscle and adipose organ axis. In this chapter, we focused on the overall impact of PE on WAT morphological, metabolic and inflammatory features, on the cross-talk between skeletal muscle and WAT as well as on the potential mediators of this process, providing an overview of the effects of PE on the obesity-related underlying pathways.

Central obesity associates with cardiovascular pathology and death. Although it constitutes a component of the metabolic syndrome, there are obese people without other cardiometabolic risk factors and there are normal weight people with cardiometabolic risk factor clustering, indicating that the problem may be another rather than obesity itself. It appears that more than the amount of accumulated fat, large adipocytes and fat deposition in other tissues, such as the liver, indicate metabolic disease. There is an impressive overlap between Cushing’s syndrome and metabolic syndrome. Stress reactions appear in a variety of forms, one of them particularly serious in its consequences, the defeat reaction, in which there is a marked activation of the hypothalamus-pituitary-adrenal axis with the production of cortisol. Psychosocial chronic stress, particularly subordinate stress, promotes an increase of cortisol production. This excess of cortisol, with time, leads to a clinical status of metabolic syndrome (central obesity, hypertension, dyslipidemia and insulin resistance). This chain of reactions and events appears to be an important factor in the association between social-economic status and health, as unemployed, refugees, ethnic minorities, homeless people, humiliated workers and a huge proportion of women across countries, small areas, social classes and income distribution, suffer from this type of chronic stress and have poor health, namely cardiometabolic diseases and depression. Adverse effects of central obesity are partly directly attributable to obesity itself, but a large part of those effects is probably due to cortisol. More important than to reduce obesity will be, therefore, to prevent stress and cortisol excess.

More than one decade ago, the International Association of Research on Cancer reported that obesity increases the risk in the development of several cancers. With the increasing epidemic rates that we face today, obesity is a major risk for cancer development. In fact, despite the increasing awareness of the public to cancer risk factors, the prevalence of several types of cancer remains high. Nevertheless, the mechanisms behind this association are not clear. Clinical and preclinical evidence indicate that obesity stands together with disturbed metabolism, insulin resistance, oxidative stress, chronic inflammation, abnormal presence of adipokines, growth factors and hormones, enhanced tissue fibrosis and imbalanced angiogenesis. Accordingly, obesity promotes a proinflammatory phenotype, characterized by a switch in M2 to M1 macrophages and exacerbated cytokine release, increased circulating levels of glucose, free fatty acids and hormones (namely insulin or leptin) and reduced circulating levels of adiponectin. All these features are often observed in neoplasia, suggesting a strong link between these two pathological conditions. This chapter highlights these putative mechanisms underlying the obesity-cancer interplay. We will tackle the processes that are imbalanced in obesity and can affect cancer development and progression, both at a systemic level as well as at local tumor environment. Identifying the features that characterize the obesity-associated cancer is mandatory for developing novel therapeutic strategies, which will definitely enhance quality of life and survival of these patients and reduce the concomitant economic burden of national healthcare systems.

Ageing is an unavoidable process that along time conduces to the loss of function of cells and tissues. Age-related modifications culminate in disease and death of the organisms. Life expectancy of humans has steadily increased in the last 50 years and the incidence of age-associated disease has increased too. Among the timedependent changes that afflict the aged individuals, obesity has gained a great importance. Adiposity increases in older individuals and tends to accumulate in visceral space, creating a metabolic threat that, together with senescence-related cell modifications, results in tissue degeneration increment and disease. In this chapter, the contribution of obesity to the ageing phenotype is discussed with a special focus on the senescence of adipose cells. In the final part of the chapter, strategies directed to mitigate the effects of obesity in old individuals that include bariatric surgery, nutritional and pharmacological interventions are presented.