Introduction

Non-communicable diseases (NCDs) remain the largest contributors to excess death globally. According the World Health Organization (WHO), NCDs are responsible for 41 million deaths per year—a staggering 74% of all global deaths [117]. In terms of mortality, the six main classes of NCDs are cardiovascular disease (CVD), cancer, chronic respiratory diseases (CRD), diabetes and kidney diseases, digestive diseases, and neurological disease. In addition to being leading causes of excess death, NCDs are major contributors to global disease burden, with an estimated 1.62 billion disability-adjusted life years (DALYs) attributed to NCDs in 2019 [34]. This includes not only the six high-mortality classes of NCDs, but also other disease classes that lead to a significant reduction in quality of life, e.g., mental and musculoskeletal disorders. To date, there is no definite cure for the vast majority of NCDs, and long-term treatment is often required for disease management. The high incidence combined with a high cumulative treatment cost results in a tremendous financial burden on health systems and economic development worldwide, with an estimated total cost of $30 trillion globally between 2011 and 2030.

The causes of NCDs vary, but aside from genetic disorders, they are generally a combination of genetic predisposition and lifestyle factors. Strikingly, almost half (48%) of global deaths can be attributed to risk factors associated with an obesogenic lifestyle or predisposition (dietary and metabolic risk factors as well as low physical activity) [34]. Simply being overweight (defined by the WHO as a BMI ≥ 25) incurs a significant risk of death and disease by itself: high (BMI ≥ 25) body mass index (BMI) is associated with 8.52% of all deaths globally [16], and the WHO estimates that overweight and obesity are the fourth most common risk factors for NCDs in Europe [18].

Overweight and obesity (defined by the WHO as BMI ≥ 30) result from an imbalance in energy intake and expenditure. Excess nutrients are stored in adipose tissues—a physiological function which serves as a crucial buffer to ensure energy availability in times of need (e.g., famine). However, a chronic net caloric surplus will lead to uncontrolled adipose tissue hypertrophy beyond the limit of healthy adipose tissue expansion. This leads to adipocyte stress and consequently to adipose tissue inflammation and fibrosis. If not controlled, this local inflammation will spill over to other organs and will affect the whole body (a process also known as “Metaflammation”) with detrimental systemic consequences, such as insulin resistance and hyperglycemia, high blood triglycerides, low LDL levels, and hypertension. Each of these conditions may constitute a disease on their own, but often several occur simultaneously. A coincidence of at least three of these conditions is collectively termed metabolic syndrome.

Over the last decades, overwhelming evidence has been published linking obesity with a plethora of disorders and diseases. Although for some diseases obesity appears to be inconsequential or even protective, the pathogenesis of the vast majority of NCDs is negatively affected by excess adiposity in some way. A literature review of each NCD included in the Global Burden of Disease [34] 2019 study showed a positive association with obesity for 71 out of 95 disorders/diseases (74.7%), while only six showed a negative association (6.3%) (Fig. 1, Supplementary Table 1).

Fig. 1
figure 1

Scheme of different classes of NCDs which have significant association with overweight and obesity. Image created with BioRender (https://www.biorender.com/)

Full size image

Overweight and obesity already affect a significant portion of the global population with 43% being overweight and 16% being obese [118]. High-income countries are particularly affected: the corresponding rates for adults in the USA are 73.6% and 42.5% [27], while the rates in Europe are 59% overweight and 23% obese [18]. Alarmingly, the increasing obesity rates are evident also in low- and middle-income countries, which have fewer resources at hand to cope with the concomitant load on healthcare services. Thus, preventing or mitigating the increasing obesity rates would be an important strategy for reducing the severe burden of NCDs on global health and healthcare systems.

Here, we summarize the broad effects of obesity and metabolic syndrome on the incidence and progression of the most common classes of NCDs.

Cardiovascular diseases

Cardiovascular diseases are the number one cause of death globally, accounting for almost a third of all deaths and almost 400 million DALYs [34]. Because of its grave consequences, high incidence, and strong correlation with obesity, cardiovascular disease is often considered the most important NCD associated with obesity.

Ischemic heart disease and stroke

Several large-scale epidemiological studies have established both a correlation as well as a causal link between obesity and ischemic heart disease and stroke. The prospective Nurses’ Health Study identified obesity a significant independent risk factor for coronary disease in middle-aged women from the USA [73], and further meta-analysis has demonstrated similar results in large cohorts of men and women in other regions of the world [9, 81]. Recently, Censin et al. [15] performed Mendelian randomization analysis of a cohort of more than 400,000 men and women, revealing a direct causal relationship between obesity and both coronary heart disease and ischemic stroke.

Obesity and atherosclerosis are intimately connected by sharing a major root cause: overnutrition. Chronic overnutrition leads to increased concentrations of very low-density lipoprotein (VLDL) and chylomicrons in the blood over time and consequently to a higher concentration of atherogenic and cholesterol-rich intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and chylomicron remnants. The deposition of LDL- and chylomicron-derived cholesterol in sub-endothelial space of the vascular wall, followed by inflammation of the surrounding tissue and formation of atherosclerotic lesions, is a key initiating step in the formation of atherosclerotic plaques [10, 58]. Simultaneously, the increased levels of triglyceride-rich lipoproteins in the blood enhances the activity of cholesteryl ester transfer protein (CETP), leading to blunted reverse cholesterol transport by increasing the exchange of cholesterol for triglycerides from HDL to LDL and VLDL, as well as lower HDL levels [58]. Additionally, chronically elevated serum nutrients (especially glucose and saturated fat) can trigger endothelial dysfunction and reduce insulin sensitivity in metabolically relevant organs, leading to impaired capacity for lipoprotein and glucose clearance, further enhancing atherogenesis [55, 58, 99, 114].

Furthermore, obesity (particularly central obesity) often leads to a state of systemic inflammation (metaflammation, see above) further enhanced by spill-over of lipids to non-adipose organs like the liver [119]. The increased levels of circulating inflammatory cytokines may also worsen the progression and stabilization of atherosclerotic plaques [44, 100, 102].

Hypertensive heart disease

The association between adiposity and hypertension has been recognized since the 1960s [51]. Hypertension increases the force required for the heart to expel blood, and chronic pressure overload can lead to ventricular thickening, hypoxia, and heart failure (hypertensive heart disease). Obesity is a major cause of hypertension, with an estimated 65–78% of hypertension cases attributed to overweight or obesity [108]. Generally, obesity is thought to initiate hypertension by impairing kidney function, via mechanisms including physical stress (compression) of the kidneys by abdominal adipose tissue, sympathetic nervous system (SNS) activation, and activation of the renin–angiotensin–aldosterone system [40]. Obesity often also leads to masked hypertension and increased pulse pressure due to increased cardiac output during everyday activities, which is not sufficiently compensated by arterial compliance [20].

Aortic stenosis

Aortic stenosis, the gradual calcification and thickening of the aortic valves, is a common vascular disease in elderly subjects affecting more than a tenth of the population above the age of 75 [87]. Aortic stenosis is a progressive disease which ultimately leads to death unless treated. Currently, the only therapeutic option for patients with aortic stenosis is aortic valve replacement. Although the precise etiology of non-rheumatic aortic valve calcification and stenosis is not fully understood, obesity has been demonstrated to constitute a significant risk factor for aortic stenosis development [60].

Recently, a direct causal link between obesity and aortic stenosis could also be established. By Mendelian randomization analysis of a cohort of over 100,000 individuals, Kaltoft et al. [50] demonstrated that an increase in BMI of only 1 kg/m2 increases the risk of aortic stenosis by over 50% (causal risk ratio 1.52).

Aortic aneurysm

Like aortic stenosis, the initiating causes of aortic aneurysms are poorly understood. The majority of aortic aneurysms occur in the abdominal aorta, affecting 4.6% of men and 1.2% of women over the age of 45 [74]. Untreated aortic aneurysm can lead to dissection and rupture of the aorta. Obesity has been associated with an increased incidence of abdominal aortic aneurysm [36], as well as increased risk of dissection in elderly patients [110].

Aneurysm of the thoracic aorta is less common but is a relatively frequent complication in patients with Marfan’s disease. A recent study surprisingly demonstrated that obesity is frequent in Marfan’s disease patients, and that obese patients with Marfan’s disease more often suffer from aortic complications [121], although a causal relationship has not yet been established.

Chronic respiratory diseases

Obesity has been shown to increase the risk of childhood asthma [31, 35, 122], and weight loss intervention has been shown to improve lung function and asthma control in asthmatic children as well as adults [93]. Surprisingly, maternal obesity also significantly increases the risk of developing asthma by 2–3% for each maternal BMI point [24]. The precise mechanism behind the link between obesity and asthma is not known. However, adipose tissue inflammation is increased in obese asthmatic patients compared to obese controls [111], and circulating IL-6, which is in part produced by adipose tissue and is elevated in obesity [21, 76], is associated with asthma severity [92]. Additionally, metabolic dysfunction is a stronger predictor of asthma development than fat mass in obesity [93]. These findings suggest an important role of inflammation in obesity-related asthma.

Diabetes

Type II diabetes (T2D), or adult-onset diabetes, is the most common comorbidity in obesity: severe obesity incurs a lifetime risk of developing T2D of 70–75% [80]. Furthermore, 80% of patients with T2D are obese [8]. The T2D-related burden on individuals as well as health care systems is enormous: more than 6% of the world’s population have T2D, and over 1 million deaths per year can be attributed to the disease [53]. As with atherosclerosis, the causal link between obesity and T2D is well understood. The precise mechanisms behind T2D development in obesity are less clear, but evidence suggests a combination of at least three factors: (1) increased insulin resistance due to chronic adipose tissue inflammation and dysregulation of adipokine secretion (e.g., adiponectin and plasminogen activator-1); (2) increased hepatic gluconeogenesis; and (3) pancreatic β-cell dysfunction [57].

A link between obesity like T2D appears to be logical; however, there is also a connection between obesity and Type I diabetes. Magnus et al. [71] showed that both paternal and maternal obesity increases the likelihood of T1D development in the offspring. Interestingly, this was not linked to maternal gestational body weight, suggesting that parental lifestyle may be a confounding factor. Additionally, Zucker et al. [123] found that a BMI increase of 5 kg/m2 during adolescence increases the risk of T1D by 35% in early adulthood. How adiposity may increase the risk of autoimmunity is still unknown.

Digestive diseases

Hepatosteatosis and cirrhosis

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by excessive fat accumulation in the liver. If left untreated, it can progress into metabolic dysfunction-associated steatohepatitis (MASH) and liver failure. This occurs through multiple pathways that induce lipotoxicity/lipid spillover and consequently inflammatory activation, e.g., ER and oxidative stress and mitochondrial dysfunction [68]. In turn, MASH can lead to further complications such as fibrosis, cirrhosis, and hepatocellular carcinoma. Overnutrition is the primary cause of MASLD, and obesity or overweight is one of the five cardiometabolic criteria for MASLD diagnosis. The prevalence of MASLD in overweight and obese patients is around 70–75% [97]. The degree and prevalence of steatosis increases with BMI, and for morbidly obese patients, the rate of steatosis has been reported to be above 90%. Cirrhosis, i.e., irreversible end-stage liver disease, has been reported in 9–12% of morbidly obese patients [2, 85]. As mentioned above (see Ischemic heart disease and stroke), caloric intake exceeding the physiological capacity of storage in adipose tissues leads to spill-over in other organs, including the liver. Consequently, weight loss leads to a reduction in hepatic steatosis in MASLD patients in a dose-dependent manner [22].

Inflammatory bowel disease

The major types of inflammatory bowel disease are ulcerative colitis (UC) and Crohn’s disease (CD). Neither disease have a known cause, and while the symptoms (e.g., abdominal pain, diarrhea, fever, and weight loss) are similar, they are distinct diseases with differing etiology. CD is typically characterized as a chronic inflammatory disorder, while UC is believed to be an autoimmune disease. Data obtained from the Nurses Health Study II revealed a significant association with obesity and CD [52], and other studies have shown a more rapid clinical course in overweight patients compared to controls [41]. The impact of obesity on CD development seems to be more pronounced when obesity is established at a young age [43]. As the fundamental cause of CD is unknown, it is also not clear how obesity increases the risk of it. However, mechanisms such as gut inflammation via intestinal dysbiosis, and obesity-related systemic inflammation, have been proposed [56]. The same analysis of the Nurses Health Study II that revealed an association between obesity and CD could not identify any increased risk of UC in obese subjects [52].

Pancreatitis

Gallstones are one of the most common risk factors for acute pancreatitis and is the primary cause of the disease in 38% of patients [115]. As obesity (especially central obesity) is a major risk factor for developing gallstones [90], obesity also increases the risk of acute pancreatitis [116]. However, other consequences of obesity are independent risk factors for acute pancreatitis. Hypertriglyceridemia, which is common in obese patients, can directly cause acute pancreatitis [30], while type 2 diabetes increases the risk of developing the disease [32]. Additionally, obesity has been shown to increase the severity of acute pancreatitis regardless of the cause [54].

Neurological diseases

Overweight and obesity have been linked to cognitive impairment in numerous studies [112], as a consequence of brain atrophy, neuroinflammation, hypoperfusion, and altered brain metabolism [25, 83]. Alarmingly, there is also mounting evidence that adiposity and its co-morbidities influence both the development and progression of the most common neurodegenerative diseases.

Alzheimer’s disease

Several studies have identified an association between mid-life obesity and Alzheimer’s disease (AD) diagnosis later in life [95]. In contrast, low BMI has been associated with an increased rate of AD diagnosis at a 1–3 year follow-up in elderly patients [82]. However, it has been suggested that this may be due to weight loss being an early consequence of disease onset. In a study with a shorter follow-up time (18 years), obesity at 70 and 79 years was associated with an increase in AD incidence in women [39].

Interestingly, diabetes also increases the risk of AD. A meta-analysis pooling the effects of obesity, diabetes, and abnormal glucose and insulin levels found stronger effect size for AD than obesity alone, suggesting that metabolic syndrome as a consequence of obesity might be a stronger risk factor for AD that obesity per se [96].

Parkinson’s disease

Although several studies examining a potential relationship between BMI and the risk of Parkinson’s disease (PD) have not consistently found an association with obesity and PD [1, 69, 88, 101]. However, abdominal obesity (waist circumference) and body shape index have been found to significantly increase the risk of PD [47, 89]. Importantly, high waist circumference is associated with increased PD risk even in normal weight patients [89], suggesting that abdominal obesity, but not high BMI per se, is a risk factor for PD. Interestingly, type 2 diabetes, which is strongly correlated with abdominal obesity, is also a strong risk factor for PD [6].

Multiple sclerosis

In contrast to PD, the connection between obesity and multiple sclerosis (MS) is clear. Obesity in either childhood, adolescence and early adulthood, has been shown to significantly increase the risk of MS later in life [42, 77, 78]. Importantly, a recent Mendelian randomization study found a causal association between both BMI and visceral adiposity [75]. Obesity seems to not only increase the risk of developing MS, but also to affect disease outcome, and there is an association between high BMI and disease severity as well as poorer outcomes [70].

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is one of the few examples of NCDs in which obesity appears to be protective. Several studies have demonstrated a positive correlation between ALS survival and obesity or an inverse correlation between BMI and ALS progression [19, 28, 67]. Surprisingly, even diagnosis of type 2 diabetes may be associated with a reduced ALS rate. The cause of this association is unknown, but since weight loss is common during ALS progression and is associated with poor prognosis [49, 67, 79], it is possible that a larger “energy reservoir” at disease onset could prolong the health span of ALS patients.

Cancer

There is a well-established link between many types of cancer and obesity. With some exceptions (e.g., testicular cancer and non-melanoma skin cancer), obesity correlates positively with the incidence of most types of neoplasms (see Supplementary Table 1). Globally, 4–8% of all new cancer diagnoses in adults and between 5 and 20% of all cancer deaths have been attributed to obesity [5, 13, 34, 113]. However, some cancers show particularly strong association with increased BMI—especially gastrointestinal, uterine, kidney, pancreatic, and breast cancers [4, 5, 61]. It is not known exactly how obesity increases the risk of cancer, but several mechanisms have been proposed. In obesity, increased aromatase activity enhances estradiol production, which can have a pro-mitogenic effect in some tumors. Obesity also often leads to elevated levels of insulin and free IGF-1, which also enhances mitogenesis in cancer cells [107]. Additionally, altered secretion of pro- and anti-inflammatory cytokines and adipokines may lead to increased oxidative stress and DNA damage, resulting in higher likelihood of tumorigenesis [91]. Here, we are focusing on cancers of the GI tract, gynecological cancers, and breast cancer.

Esophageal cancer

The two most common esophageal cancers are esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma. Obesity is a major risk factor for EAC, with severely obese patients exhibiting an almost fivefold increased risk of EAC development [61]. This may at least partially be explained by increased rates of gastroesophageal reflux disease (GERD) and Barret’s esophagus. Moreover, one meta-study using pooled data from 12 epidemiological studies found significant correlation between obesity and EAC even in patients without diagnosed GERD [46].

Colorectal cancer

Colorectal cancer (CRC) ranks third in cancer prevalence and second as a cause of cancer-associated deaths globally [33]. An increase in body weight of 10 kg increases the risk of developing CRC by 8%. Both weight gain in adulthood as well as early-life obesity significantly increases the risk of CRC [29, 106]. Interestingly, bariatric surgery for weight loss has been shown to reduce the risk by approximately 27% [120]. The exact mechanisms that link overweight/obesity with CRC are so far unknown, but it has been speculated to be due to systemic inflammation, dysregulated adipokine secretion, and altered gut microbiota [120]. Moreover, it has been suggested that the correlation between obesity and CRC may be underestimated, as many patients lose weight prior to cancer diagnosis, and the reported BMI in many studies is measured close to diagnosis [72].

Gynecological cancers

Among the cancers affecting the female reproductive system, carcinoma of the endometrium is the most common and shows the strongest correlation with obesity [109]. Obesity increases both the risk of developing endometrial cancer, as well as the severity of the disease once diagnosed. For each 5 kg/m2 of BMI, the risk of developing endometrial cancer increases by roughly 50%, and the relative risk of mortality after diagnosis is 2.53 for obese women, and 6.25 for morbidly obese women. As mentioned above, adipose tissues express aromatase, and total aromatase activity is increased in obesity. Estrogens act as powerful mitogenic and mutagenic factors in endometrial tissue, and the increased levels of estrogens in obese postmenopausal women have been proposed as one of the causal mechanisms behind the strong correlation between obesity and endometrial cancer [86].

Other gynecological cancers have a less clear association with obesity: While some studies have identified obesity as a risk factor for ovarian cancer, the overall evidence is weak [23, 84]. Overweight and obesity have been associated with increased incidence of cervical cancer, but recent studies suggest that this might be due to underdiagnosis of cervical precancer in obese individuals, as well as lower rates of participation in cancer screening [17, 104].

Breast cancer

The relationship between obesity and breast cancer appears to depend largely on cancer type and menopausal status. In premenopausal women, obesity is inversely correlated with hormone receptor-positive (HR+) breast cancer risk. In postmenopausal women, however, obesity is positively correlated with HR+ cancer risk [94]. Interestingly, obesity in premenopausal women is associated with a decreased level of circulating estradiol, while the opposite is true for postmenopausal women [26]. In this context, it is of interest that aromatase-derived estrogen from peripheral tissues (especially adipose tissue) is the major source of circulating estradiol after menopause [38]. This difference in adipose tissue-derived estrogen production provides an intriguing explanation for the contrasting risk ratios of HR+ breast cancer in pre-and post-menopausal women. In contrast, HR- breast cancer incidence is strongly correlated to obesity in premenopausal women, but not in postmenopausal women, while obesity increases the risk of inflammatory breast cancer in both patient groups [94]. Obesity is associated with poorer outcomes regardless of breast cancer types and patient groups [64]. Other obesity-related mechanisms, such as low-grade systemic inflammation and increased secretion of pro-angiogenic and pro-mitogenic cytokines, have been proposed to contribute to the over-all detrimental effects of obesity in breast cancer [94].

Pancreatic cancer

Several meta-analyses have found a significantly increased risk of pancreatic cancer in obese individuals [7, 59, 98]. Pancreatic cancer is the 11th most common type of cancer and has an extremely poor prognosis with a survival rate of around 6% [48]. Interestingly, weight loss induced by bariatric surgery has been shown to significantly reduce the risk of pancreatic cancer [103].

The obesity paradox

Although an obese state generally causes an increased metabolic, inflammatory, and mechanical load on the body, increased BMI can sometimes be beneficial. This effect is known as the obesity paradox. In some cases, the different effects of obesity can be easily explained on a purely mechanical basis: for example, obesity is strongly associated with increased lower back pain, but not neck pain, clearly reflecting the mass distribution in obese patients and the resulting mechanical load of the relevant body parts. Similarly, the positive correlation of obesity with abdominal hernias, but negative correlation with inguinal and femoral hernias, may also be explained in anatomical terms. In other cases, the differences are not easily understood. The abovementioned discrepancy between ALS and other neurological disorders has so far defied explanation, and the mechanism behind the protective effect of obesity on squamous cell carcinoma of the esophagus, but detrimental effect on esophageal adenocarcinoma is likewise unclear.

The obesity paradox has been recognized in CVD patients for over two decades yet remains controversial [62]. Originally described in heart failure patients, a beneficial effect of moderately increased BMI, body fat, or waist circumference has also been shown in patients with coronary artery disease and peripheral artery disease [63]. However, recent research using updated and improved adiposity indices (e.g., hip-to-waist ratio) found no protective effect of increased adiposity [12]. Possibly, the earlier reports on the obesity paradox in CVD patients may have been a consequence of reduced cardiovascular fitness, sarcopenia, and increased frailty (by having less stored energy reserves) in the patients in the non-obese groups [14, 65].

Similarly, the obesity paradox has also been observed among cancer patients. While it is clear that obesity is a risk factor for developing many types of cancers, several studies have shown a correlation between BMI and overall survival in cancer patients after diagnosis [11, 45, 105]. However, BMI may be a poor read-out for adiposity in this case: sarcopenic patients with obesity have been shown to have the worst prognosis among cancer patients, suggesting that there might be no cancer obesity paradox when using more appropriate measures for adiposity [37]. Additionally, the apparent cancer obesity paradox has been suggested to be a product of methodological issues, including selection bias, collider stratification bias, and reverse causality [66].

Interestingly, in some cases, maternal obesity may also protect the offspring from developing NCDs. Alam et al. [3] found that maternal obesity reduces the risk of testicular cancer in the offspring, through so far unknown mechanisms.

Conclusions

There is a clear link between NCDs and obesity: Obesity is the leading cause for NCDs. Importantly, obesity is linked to those NCDs with grave consequences. The spectrum of diseases ranges from cardiovascular disease (myocardial infarction, stroke, hypertension, leading to sudden death and heart failure), metabolic disorders (as expected), and certain cancers (e.g., colorectal and gynecological cancers).

Thus, it is of outmost importance to tackle obesity, and there is an urgent need for pharmacological therapies. The new incretin-based drugs (“ozempic”) have enormous success reaching almost levels of bariatric surgery. However, these are considered to be “forever” drugs, and other novel approaches are urgently needed for alternative and synergistic treatments.