An overview of obesity-related complications: The epidemiological evidence linking body weight and other markers of obesity to adverse health outcomes

Abstract

Obesity is a highly prevalent chronic multisystem disease associated with shortened life expectancy due to a number of adverse health outcomes. Epidemiological data link body weight and parameters of central fat distribution to an increasing risk for type 2 diabetes, hypertension, fatty liver diseases, cardiovascular diseases including myocardial infarction, heart failure, atrial fibrillation, stroke, obstructive sleep apnoea, osteoarthritis, mental disorders and some types of cancer. However, the individual risk to develop cardiometabolic and other obesity-related diseases cannot entirely be explained by increased fat mass. Rather than excess fat accumulation, dysfunction of adipose tissue may represent the mechanistic link between obesity and adverse health outcomes. There are people living with obesity who seem to be protected against the premature development of cardiometabolic diseases. On the other hand, people with normal weight may develop typical obesity diseases upon dysfunction of adipose tissue and predominantly visceral fat distribution. The mechanisms linking impaired function of adipose tissue in people with obesity include adipocyte hypertrophy, altered cellular composition, limited expandability of safe subcutaneous fat stores, ectopic fat deposition in visceral depots, the liver and other organs, hypoxia, a variety of stresses, inflammatory processes, and the release of pro-inflammatory, diabetogenic and atherogenic signals. Genetic and environmental factors might contribute either alone or via interaction with intrinsic biological factors to variation in adipose tissue function. There are still many open questions regarding the mechanisms of how increased body weight causes obesity-related disorders and whether these pathologies could be reversed. Evidence-based weight loss interventions using behaviour change, pharmacological or surgical approaches have clarified the beneficial effects of realistic and sustained weight loss on obesity-related complications as hard outcomes. This review focusses on recent advances in understanding epidemiological trends and mechanisms of obesity-related diseases. PLAIN LANGUAGE SUMMARY: Obesity is a chronic complex and progressive disease characterized by excessive fat deposition that may impair health and quality of life. Worldwide, the number of adults living with obesity has more than doubled since 1990. Obesity may lead to reduced life expectancy, because it increases the risk for type 2 diabetes, cardiovascular diseases (e.g., myocardial infarction, high blood pressure, stroke), fatty liver diseases, musculoskeletal diseases, chronic respiratory diseases, depression and certain types of cancer. However, not every person with obesity develops these diseases. For better prevention and treatment, it is important to understand the mechanisms linking high fat mass to obesity related diseases. It has become clear that fat mass alone cannot explain the higher risk of obesity complications. People with obesity can have either high or low risk of developing complications. Compared to people with a low risk for obesity complications those with a high risk to develop obesity related diseases are characterized by higher central fat deposition in the abdominal region, on average bigger fat cells, higher number of immune cells in adipose tissue and altered signals released from adipose tissue that may directly affect the brain, liver, vasculature and other organs. Both inherited and environment factors may cause these abnormalities of adipose tissue function. However, weight loss through behaviour changes (e.g., lower calorie intake, higher physical activity), medications or obesity surgery can improve health, quality of life and reduce the risk for obesity related diseases.

Keywords: adipose tissue; cardiometabolic diseases; complications; obesity.

FIGURE 1

Obesity as a multisystem disease. Selected complications that are most strongly related to obesity. MAFLD, metabolic dysfunction‐associated fatty liver disease; OSAS, obstructive sleep apnea syndrome.

FIGURE 2

Association between type 2 diabetes and body mass index (BMI) categories. Data from the US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD) and National Health and Human Nutrition Examination Surveys (NHANES) revealed that with increasing BMI, the frequency of type 2 diabetes increases.,

FIGURE 3

Effects of weight loss (%) on risk factors, and obesity‐related comorbidities and complications. The figure has been adopted from . MAFLD, metabolic dysfunction‐associated fatty liver disease; OSAS, obstructive sleep apnea syndrome.

FIGURE 4

The phenotype of metabolically healthy obesity. Individuals with this subphenotype of obesity are characterised by lower liver and visceral fat, but higher subcutaneous leg fat content, greater cardiorespiratory fitness and physical activity, insulin sensitivity, lower levels of inflammatory markers, and normal adipose tissue function compared to patients with metabolically unhealthy obesity.

FIGURE 5

Development of adipose tissue dysfunction. With a chronic positive energy balance and body weight gain, adipose tissue expands due to increased nutrient flux. Under healthy conditions, adipose tissue plasticity allows for an expansion of adipose tissue that is characterised by both hyperplasia and hypertrophy. In the pathogenesis of adipose tissue dysfunction, adipocytes primarily respond to the higher demand for energy storage by increasing their size (adipocyte hypertrophy). Adipocyte hypertrophy contributes to cellular composition changes, activation of stress kinase signalling, inflammatory, autophagy, apoptosis pathways, increased tissue insulin resistance, altered lipolysis and lipogenesis, changes in extracellular matrix proteins and unfolded protein response. These altered pathways are reflected by an altered gene and protein expression signature of dysfunctional adipose tissue (example molecules are shown).

FIGURE 6

Obesity and cancer. Obesity is associated with an increased risk to develop specific types of cancer with differences between men and women., Proposed mechanisms linking obesity and adipose tissue dysfunction to increased risk to obesity‐related cancers.