Obesity and the risk of cardiometabolic diseases

Abstract

The prevalence of obesity has reached pandemic proportions, and now approximately 25% of adults in Westernized countries have obesity. Recognized as a major health concern, obesity is associated with multiple comorbidities, particularly cardiometabolic disorders. In this Review, we present obesity as an evolutionarily novel condition, summarize the epidemiological evidence on its detrimental cardiometabolic consequences and discuss the major mechanisms involved in the association between obesity and the risk of cardiometabolic diseases. We also examine the role of potential moderators of this association, with evidence for and against the so-called ‘metabolically healthy obesity phenotype’, the ‘fatness but fitness’ paradox or the ‘obesity paradox’. Although maintenance of optimal cardiometabolic status should be a primary goal in individuals with obesity, losing body weight and, particularly, excess visceral adiposity seems to be necessary to minimize the risk of cardiometabolic diseases.

Key points

• Obesity has reached pandemic proportions, which in turn has led to an increase in the risk of concomitant cardiometabolic conditions.

• Obesity is an evolutionary mismatch between our ancient, genetically determined physiology and the modern diet and lifestyle; not only did we not evolve to have obesity but we never evolved to cope with its numerous associated maladaptations, such as massive adipocyte hypertrophy to accommodate excess fat.

• Obesity is associated with both excess quantity and dysfunction of white adipose tissue, particularly visceral adipose depots.

• ‘Metabolically healthy obesity’ often reflects a transitionary stage to an unhealthy phenotype.

• Sustained body weight control in individuals with obesity improves their cardiometabolic risk status.

Glossary

Adipocytokine

From the Greek adipo (fat), cytos (cell) and kinos (movement); also termed ‘adipokine’. Cytokine secreted by adipose tissue.

Adipogenesis

Formation of new adipocytes from precursor cells.

Aerobic exercise

Also known as endurance exercise. Exercise that is performed for more than a few minutes and preferentially involves aerobic metabolism for energy production (for example, brisk walking, bicycling or swimming).

Bariatric surgery

Also known as weight-loss surgery. Various surgical procedures (such as gastric bypass) performed on people with obesity that alters levels of digestive hormones responsible for hunger and satiety.

Cardiorespiratory fitness

The capacity of the circulatory and respiratory systems to supply oxygen to skeletal muscle mitochondria for production of the energy needed during physical activity, usually determined by treadmill or cycle-ergometer testing until exhaustion.

Damage‐associated molecular patterns

(DAMPs). Molecules that act as endogenous danger signals; they are released into the extracellular space in response to cell damage and promote inflammatory responses by binding to pattern recognition receptors.

Dual-energy X-ray absorptiometry

(DXA or DEXA). A method of measuring fat and lean (muscle and bone) mass based on the different attenuation coefficients to X-rays of soft tissue and bone.

Glycated haemoglobin

Also known as haemoglobin A1c (HbA1c). A form of haemoglobin that is produced when glucose reacts with the amino group on a haemoglobin molecule, thereby reflecting the presence of hyperglycaemia, which is often indicative of diabetes mellitus.

Heart failure with preserved ejection fraction

A type of heart failure that occurs when the muscle in the left ventricle stiffens and has a lower relaxation capacity. Patients have signs and symptoms of heart failure despite having a normal, or near-normal, left ventricular ejection fraction (≥50%).

Hyperplasia

An increase in the number of cells in an organ or tissue (by recruitment and differentiation of new precursor cells) that seem normal under a microscope (as opposed to dysplasia) and result in an increase in organ or tissue size.

Hypertrophy

An increase in the size of cells in an organ or tissue as a result of elevated synthesis of structural components (not of cellular swelling) that can result in an increase in organ or tissue size.

Integrated stress response

An evolutionarily conserved intracellular signalling network that helps the cell, tissue and organism to adapt to a variable environment and maintain health.

Lipoapoptosis

Ectopic lipid overload can interfere with cell functions and induce apoptosis, thereby contributing to gradual organ failure.

Lipodystrophy syndromes

Heterogeneous group of diseases characterized by the selective absence of adipose tissue, where the primary defect is the loss of functional adipocytes, leading to lipotoxicity, severe dyslipidaemia or insulin resistance.

Lipotoxicity

When the storage capacity of the white adipose tissue is exceeded, ectopic fat storage occurs in several organs (skeletal muscle, liver, heart and pancreas), leading to cellular dysfunction in these organs.

Long-chain saturated fatty acids

(LCSFAs). Fatty acids with aliphatic tails with >12 carbon atoms (for example, palmitate and stearate), resulting from the hydrolysis of neutral lipids (such as triacylglycerols stored in adipocytes). LCSFAs are also found abundantly in dairy fat, tallow, lard and palm oil.

Mediterranean diet

A diet abundant in fruits, vegetables, legumes, whole grains, olives, nuts and seeds, and containing extra-virgin olive oil, associated with frequent consumption of fish, moderate consumption of dairy products and red wine, and low consumption of red meat and isolated sugars.

Metabolic syndrome

A clustering of three or more of the following five medical conditions: abdominal obesity (as determined by waist circumference), high blood pressure, hyperglycaemia, hypertriglyceridaemia and low serum HDL-cholesterol level.

Neutral lipids

Based on their chemical characteristics, lipids can be classified into neutral (for example, triacylglycerols) and polar (such as phospholipids and glycolipids) lipids; neutral lipids are used as major energy sources and polar lipids as cell membrane components.

NLRP3 inflammasome

Cytosolic multiprotein oligomer involved in the innate immune response, responsible for the activation of pro-inflammatory responses.

Obesity class

Class 1 is defined as BMI of 30 to <35 kg/m², class 2 as BMI 35 to <40 kg/m² and class 3 as BMI ≥40 kg/m².

Omentum

The layers of peritoneum (the serous membrane forming the lining of the abdominal cavity) that surround abdominal organs: the greater omentum is a large apron-like fold of visceral peritoneum that hangs down from the stomach, whereas the lower omentum hangs down from the liver.

Pattern recognition receptor

A type of receptor that recognizes damage-associated molecular patterns, as well as molecular structures produced by microbial pathogens.

Physical activity

Any bodily movement produced by skeletal muscles that requires energy expenditure (for example, walking). The WHO recommends that adults engage in regular (150–300 min per week) moderate or vigorous aerobic physical activities (such as brisk walking).

Physical exercise

Also termed ‘exercise training’ or simply ‘exercise’. A subset of physical activity that is planned, structured and repetitive and has a final or an intermediate objective of improving or maintaining fitness or health outcomes.

Sarcopenia

Derived from the Greek ‘sarx’ (flesh) and ‘penia’ (loss). The age-induced (or sometimes disease-induced) loss of muscle mass and function.

Senescence-associated secretory phenotype

Phenotype associated with senescent cells, which secrete high levels of pro-inflammatory cytokines, chemokines and other molecules.

Severe obesity

Also known as obesity class 3; BMI ≥40 kg/m². The term ‘morbid obesity’ was also formerly used to define a BMI of ≥40 kg/m² (or BMI ≥35 kg/m² when accompanied by obesity-related conditions).

Systemic, low-grade, chronic inflammation

A sterile chronic inflammation characterized by the activation of immune components that are often distinct from those engaged in acute immune responses, potentially causing major alterations in all tissues and organs as well as in normal cellular physiology and increasing the risk of various non-communicable diseases across the lifespan of the individual.

γδ T cells

A small subset of T lymphocytes that express heterodimeric T cell receptors (TCRs) composed of γ and δ chains, as opposed to the classical CD4⁺ T helper cells or CD8⁺ cytotoxic T cells, which express αβ TCRs.