The Root Causes: Biology and Environment

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Medical Disclaimer: This content is for educational purposes only and does not constitute medical advice, diagnosis, or treatment. Information is based on current medical literature and clinical guidelines but may not apply to your specific situation. Individual responses vary based on personal medical history and concurrent conditions. Always consult qualified healthcare providers before starting new treatments and for all medical decisions. Never delay seeking medical care based on content you have read. If experiencing a medical emergency, seek immediate medical attention.

These articles provide education to enhance your healthcare partnership. All treatment decisions should involve your healthcare team. Use this knowledge to have informed discussions, not replace medical care.

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In Brief

Metabolic syndrome looks like five different abnormalities, but in most people it is driven by a single upstream process. Visceral fat, the fat that wraps around abdominal organs, becomes biologically inflammatory as it expands. It releases free fatty acids and inflammatory signals that flood the liver, disrupt insulin signalling in muscle, and damage the lining of blood vessels. Modern environments (calorie-dense engineered foods, sedentary work, short sleep, and chronic stress) accelerate every step. The same biological loops that amplify dysfunction can work in reverse, which is what makes intervention possible.

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Article 1 explained what metabolic syndrome is and why the clustering matters. This article explains why it develops: what is actually happening, biologically, beneath the surface of those abnormal numbers.

The five components track back to one process, and it shows in how they relate. Elevated triglycerides and low HDL are the same liver biology measured two different ways. Elevated blood pressure shares its drivers with the rest of the syndrome. Elevated fasting glucose reflects pancreatic compensation that has been under way for years.

The exact contribution of each pathway varies from person to person, and people develop the components at different rates and in different sequences. But most converge on the same biology: visceral adiposity, insulin resistance, chronic low-grade inflammation, and the metabolic consequences that follow.

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Why This Became Epidemic

Modern environments expose ancient metabolic systems to conditions they were not designed to regulate continuously. Human metabolism evolved for intermittent food availability and constant physical activity. Calorie-dense engineered foods, hours of sitting, and short sleep are recent enough that our biology has not had time to adapt.

No single environmental factor explains the epidemic. Diet, inactivity, sleep loss, and stress each contribute, converging on the same metabolic pathways and producing the same underlying biology through different combinations of exposures.

The components of metabolic syndrome are not a moral failing. They are a predictable physiological response to environments human biology was never designed to handle.

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Visceral Fat: The Central Driver

Metabolic syndrome begins as a problem of dysfunctional energy storage: what happens when the body’s capacity to safely contain excess energy is exceeded. Not all fat behaves the same way, and the most important distinction is not how much fat someone carries but where it is stored.

Subcutaneous fat, the layer beneath the skin, is comparatively less metabolically active. It drains into the systemic circulation, where any signals it releases are diluted before reaching the major organs.

Visceral fat, the fat that wraps around the liver, pancreas, and intestines, behaves entirely differently. It is metabolically active, hormonally complex, and drains directly into the portal vein, meaning whatever it releases reaches the liver in high concentrations before the rest of the body is exposed. Relatively small increases in visceral adiposity can therefore produce disproportionately large metabolic effects.

The Framingham Heart Study used CT scanning to quantify fat compartments and correlate them with metabolic risk.[1] Visceral fat tracked strongly with every component of metabolic syndrome, more strongly than subcutaneous fat, and the association held even after accounting for overall body size.

Fat compartment	Association with metabolic syndrome	Association with insulin resistance
Visceral adipose tissue	Strong, independent[1]	Strong, independent[1]
Subcutaneous abdominal fat	Weak[1]	Weak[1]

Where fat is stored matters more metabolically than how much fat is carried, a distinction that BMI alone cannot capture. BMI cannot distinguish muscle from fat or identify where fat is stored, so two people with identical BMI can have very different metabolic profiles. Waist circumference, which correlates with visceral fat, predicts metabolic risk far better.[1] South Asian populations in particular tend to develop significant visceral adiposity at lower BMI, which is why lower waist cutoffs apply to them.

Waist circumference	Men	Women
Elevated risk	≥94 cm (37 in)	≥80 cm (31.5 in)
Substantially elevated risk	≥102 cm (40 in)	≥88 cm (35 in)

Source: IDF/AHA/NHLBI harmonised criteria.[2]

Waist circumference is measured at the top of the iliac crest (the top of the hip bone), on bare skin, at the end of a normal exhale. Technique matters: some protocols instead use the midpoint between the lowest rib and the iliac crest, and different methods can shift the reading by an inch or more, which is why consistency matters more than any single measurement.

A 2025 meta-analysis of 17 cohort studies (over 824,000 participants) found that the highest category of the visceral adiposity index (a score calculated from waist circumference, BMI, triglycerides, and HDL) carried a 55% higher relative risk of cardiovascular disease than the lowest.[3]

Visceral adiposity explains most cases of metabolic dysfunction, but not all. The quantity of visceral fat and its inflammatory activity are not always perfectly correlated; some people develop significant insulin resistance at modest BMI because of genetic susceptibility, fat distribution, or low muscle mass. The consistent pattern is that adipose dysfunction, not weight alone, drives the syndrome. Waist circumference often changes meaningfully before total body weight shifts, which is why the tape measure is frequently a more sensitive early signal than the bathroom scale.

Hormonal changes, particularly the menopausal transition in women, can also redistribute fat from peripheral to visceral depots independently of weight change, accelerating metabolic risk during a period when body weight may appear stable.

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Why Visceral Fat Becomes Inflammatory

The danger of visceral fat is not simply its location but what happens to the tissue as it expands.

Adipose tissue is now understood as an endocrine and immune organ, not passive energy storage. When visceral fat expands beyond its healthy storage capacity, the tissue begins to malfunction. Local oxygen delivery cannot keep pace with the expanding cells, producing tissue hypoxia. Individual fat cells become stressed. Immune cells called macrophages move in, initially to clear dying cells, but their presence amplifies inflammatory signalling rather than resolving it.[5] This is how excess energy storage becomes a source of chronic systemic inflammation.

This shift in adipose biology produces measurable changes throughout the body. Fat cells release chemical messengers called adipokines that influence metabolism at a distance.[4,5] In a metabolically healthy state, the balance favours protective signals like adiponectin. In metabolic syndrome, that balance shifts: pro-inflammatory signals rise while protective signals fall.

Compound	Source	Effect on metabolism
TNF-α	Adipocytes, macrophages	Interferes with insulin signalling[5,7]
IL-6	Adipocytes, macrophages	Triggers hepatic glucose release; raises CRP production[5,7]
Free fatty acids	Adipocytes	Impair insulin signalling; increase liver triglyceride production[5,8]
PAI-1	Adipocytes	Slows clot breakdown; increases thrombotic risk[5]
Resistin	Adipocytes	Linked to insulin resistance in some studies[5]
Adiponectin	Adipocytes	Protective; enhances insulin sensitivity; reduced in obesity[5]

The clinical pattern this produces is exactly what appears in metabolic syndrome lab work. Adiponectin falls while TNF-α, IL-6, and free fatty acids rise, and the downstream lab values drift together rather than independently.

Adipose tissue also regulates appetite through hormones like leptin, which normally signals energy sufficiency to the brain. In established metabolic syndrome, leptin resistance frequently develops: leptin levels are high, but the brain responds incompletely to the signal. The result is impaired satiety, one reason sustained weight reduction is biologically harder than simple calorie arithmetic suggests.

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The Inflammatory Cascade

Once inflammation begins in visceral fat, it does not stay there. The same compounds released into circulation reach every organ system that matters for metabolic syndrome, and they affect each in different ways.

This chronic low-grade inflammation differs fundamentally from the acute inflammation of injury or infection. It operates quietly, over years, at intensities low enough that patients feel entirely well, and inflammatory markers may remain within normal reference ranges even as biologically significant inflammation drives disease progression.

Liver. Free fatty acids and inflammatory signals from visceral fat arrive at the liver in high concentrations through the portal vein. The liver responds by overproducing triglyceride-rich lipoproteins and becoming less responsive to insulin. This raises blood triglycerides, lowers HDL, and contributes to elevated CRP.[7] Fat accumulates within the liver itself, and that liver fat is not a passive byproduct. It is biologically active tissue that actively worsens insulin resistance and abnormal lipid handling, creating one of the most important reinforcing cycles in the syndrome. Fatty liver is often clinically silent for years, detectable only through imaging or incidentally elevated liver enzymes.

Skeletal muscle. Muscle is the body’s largest glucose-buffering organ; after a meal, it takes up the majority of glucose entering the bloodstream. Inflammatory signals interfere with how muscle cells respond to insulin, reducing this uptake.[6] Muscle loss with ageing compounds the problem: less total muscle means less glucose disposal capacity at the same body weight, which is one reason insulin resistance tends to worsen across the lifespan independent of dietary change.

Vasculature. Inflammatory cytokines impair the endothelium, the thin cellular layer lining every blood vessel, by reducing nitric oxide production.[8] Reduced nitric oxide means vessels cannot relax and dilate normally, contributing to higher blood pressure and accelerating atherosclerosis. Critically, endothelial dysfunction and the vascular injury it produces often begin decades before any cardiovascular event becomes clinically apparent.

Pancreas. Chronic exposure to inflammatory cytokines and elevated free fatty acids gradually impairs the insulin-producing beta cells, which compensate by working harder to keep glucose normal.[9,10]

Because insulin signalling influences nearly every major metabolic organ, dysfunction rarely remains confined to a single system.

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Insulin Resistance: Mechanism and Consequences

Insulin resistance, reduced cellular responsiveness to insulin, develops through well-characterised pathways. At the cellular level, stress-activated inflammatory pathways interfere with insulin’s signalling inside cells, impairing its ability to direct glucose uptake and metabolism.[6]

The downstream effects appear in every organ that responds to insulin:

System	Effect of insulin resistance
Liver	Impaired suppression of glucose production; increased triglyceride synthesis
Muscle	Reduced glucose uptake; impaired glycogen synthesis
Adipose tissue	Impaired suppression of lipolysis; increased free fatty acid release
Pancreas	Compensatory hyperinsulinaemia; eventual beta-cell exhaustion

A critical reframe: insulin resistance initially functions as a protective adaptation. When cells are chronically saturated with excess nutrients, reducing their responsiveness to insulin prevents further fuel overload. The problem is that this protection, sustained over years, produces its own cascade of consequences.

For years, the body compensates: the pancreas produces more insulin to overcome the resistance, holding glucose in the normal range while the dysfunction underneath keeps advancing.

This compensation has its own consequences. Elevated insulin promotes sodium retention, contributing to higher blood pressure. It stimulates the liver to produce more fat, worsening lipid abnormalities. It encourages further visceral fat deposition, intensifying the original inflammation. The very mechanism that maintains normal glucose accelerates the underlying disease. And critically, insulin resistance may produce years of elevated fasting insulin, and all its consequences, before fasting glucose becomes abnormal at all.[10]

Once compensatory capacity begins to fail, deterioration often accelerates sharply. Beta-cell exhaustion develops after years of overproduction, and when the pancreas can no longer keep up, what looked like a slow drift in glucose becomes a steep climb.

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The Environmental Drivers

Environmental factors drive the epidemic by promoting visceral fat accumulation, amplifying inflammation, and disrupting metabolic signalling. Each of the four forces below has a clear mechanism and strong supporting evidence.

Dietary Patterns

Ultra-processed foods now supply close to 60% of the calories American adults eat.[11] These products differ from minimally processed foods in ways that extend well beyond macronutrient composition. Not all processed foods behave identically; the concern is specifically with highly engineered products designed to maximise palatability and energy density while minimising satiety signalling.

The most rigorous demonstration came from a controlled NIH metabolic-ward study. Participants were given access to either ultra-processed or minimally processed diets matched for available calories, macronutrients, sugar, sodium, and fibre, so that processing itself, not nutrient content, was the variable.[12] Participants eating ultra-processed food consumed about 508 more calories daily and gained weight; those eating minimally processed food lost weight. Neither group was aware of the difference. The biological response to food involves more than calories: texture, satiety signalling, and reward pathways all matter, and ultra-processed foods appear to disrupt several of these at once.

Modern food environments bypass traditional satiety signalling by compressing large amounts of energy into small, rapidly absorbed volumes that fail to trigger the hormonal and mechanical cues the body evolved to use. Appetite regulation becomes unreliable not because of weak willpower, but because the food environment was engineered to make it so.

Large recent analyses reinforce this. A 2024 dose-response meta-analysis found that each 10% increase in the share of calories from ultra-processed food was associated with a 1.6% increase in cardiovascular event risk.[13] A 2024 umbrella review in the BMJ found convincing evidence linking ultra-processed food exposure to cardiovascular mortality, with roughly a 50% higher risk among those with the highest consumption.[14] In 2025, the American Heart Association issued a science advisory recognising ultra-processed foods as a growing public health challenge.[15]

Physical Inactivity and Sedentary Behaviour

Physical inactivity promotes metabolic dysfunction through several pathways beyond reduced energy expenditure.[16] Skeletal muscle contraction triggers the release of myokines, muscle-derived signalling molecules with anti-inflammatory and insulin-sensitising effects. Regular activity maintains myokine production; prolonged inactivity reduces it. Even brief muscle contraction meaningfully improves glucose uptake, while prolonged sitting removes that metabolic stimulus for hours at a time.

The Australian Diabetes, Obesity and Lifestyle Study found that sitting time was associated with increased metabolic syndrome risk even after accounting for structured exercise.[17] A 2016 AHA advisory confirmed that sedentary behaviour independently raises cardiovascular and diabetes risk even among people who meet activity guidelines.[18] Exercise benefits appear well before dramatic weight loss, and often in its absence entirely, because the primary mechanism is restoring the metabolic function of skeletal muscle, not burning calories.

Meeting structured exercise targets does not neutralise the metabolic effects of sitting for eight to ten hours a day. Prolonged sedentary time carries independent metabolic consequences, distinct from simply not exercising enough: metabolism responds to patterns across the whole day, not to isolated bouts of activity.

Sleep Duration and Quality

The body interprets chronic sleep loss as a biological stressor, shifting metabolism toward energy conservation and increased appetite. Experimental sleep-restriction studies show how rapidly these effects appear. In one canonical protocol, healthy young adults restricted to roughly 4 hours of sleep showed measurable metabolic deterioration:[19,20]

Parameter	Change
Glucose tolerance	~40% reduction
Insulin sensitivity	Decreased
Leptin (satiety hormone)	~18% decrease
Ghrelin (hunger hormone)	~28% increase
Evening cortisol	Elevated

These short-term effects reversed with sleep recovery, but they show direction and mechanism, and they appeared within days, before any meaningful weight change. Sleep loss alters hunger signalling independently of behaviour or willpower. A 2024 randomised trial confirmed the sustained pattern: restricting sleep to about 6 hours nightly for 6 weeks raised insulin resistance in women, independent of any change in body weight.[21] Subjective tolerance is a poor guide here: these shifts occur even in people who feel adequately rested on six hours.

Obstructive sleep apnoea deserves particular attention. It independently worsens metabolic parameters through repetitive nocturnal hypoxia and sympathetic activation throughout the night.[22] Many people with significant sleep apnoea, including many who are not overtly obese, remain undiagnosed for years despite substantial physiological effects. Loud snoring, witnessed pauses in breathing, daytime sleepiness, and blood pressure that responds poorly to medication are signals worth evaluating formally.

Chronic Psychological Stress

Chronic stress activates the hypothalamic-pituitary-adrenal axis, producing sustained cortisol elevation. The stress that matters metabolically is rarely dramatic: long work hours, financial pressure, caregiving load, persistent low-grade worry. Most people carrying it would not describe themselves as stressed, but cortisol signals are hormonal events that alter fat distribution, appetite regulation, and insulin sensitivity regardless of how the stress is subjectively experienced. Persistently elevated cortisol promotes visceral fat accumulation preferentially over subcutaneous fat.[23]

The Whitehall II study followed British civil servants for 14 years and found that chronic work stress was associated with more than a twofold increased risk of metabolic syndrome, an effect strongest among those with least control over their work conditions.[24] Stress-related eating is also partly hormonally mediated: cortisol and ghrelin interact to increase appetite and preference for energy-dense foods, which is why dietary patterns often deteriorate during periods of sustained stress even without a conscious decision to eat differently.

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Genetic Susceptibility

Genetic factors influence susceptibility to metabolic syndrome, but environmental factors largely determine whether genetic predisposition becomes clinical disease. Twin studies suggest genetic factors account for roughly 25–40% of risk.[25] Genome-wide association studies have identified specific variants, including TCF7L2, the strongest known genetic risk factor for type 2 diabetes, that affect insulin secretion and fat-cell function.[26] But identified variants explain only a fraction of total heritability, and genetic susceptibility primarily determines how strongly individuals respond to the same environmental exposures, not whether the syndrome is inevitable. The remaining 60–75% of risk reflects environment and behaviour, which makes family history a reason for vigilance rather than fatalism.

The clearest evidence that environment, not inheritance, drives the epidemic is its speed: metabolic syndrome has become common in populations whose gene pools have not changed. The environment shifted, unmasking genetic susceptibilities that were previously unexpressed.

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The Self-Amplifying Cycle

The mechanisms described above do not operate in isolation; they reinforce each other continuously, which is why metabolic syndrome tends to progress unless something deliberately interrupts the cycle.

Initial change	Secondary effect	Tertiary effect
Visceral fat accumulation	Increased inflammatory cytokine production	Worsening insulin resistance
Insulin resistance	Compensatory hyperinsulinaemia	Promotes additional fat storage
Hepatic fat accumulation	Increased VLDL production	Elevated triglycerides, reduced HDL
Endothelial dysfunction	Reduced nitric oxide	Elevated blood pressure
Sleep disruption	Increased cortisol and sympathetic activation	Worsened insulin resistance and appetite dysregulation

Many of these relationships are bidirectional. Insulin resistance promotes visceral fat accumulation, and visceral fat worsens insulin resistance. Hepatic fat impairs lipid metabolism, and dyslipidaemia promotes more hepatic fat. Each abnormality feeds the others. The syndrome often progresses gradually enough that patients normalise their worsening health, which is one reason the pattern frequently goes unrecognised until it has been operating for years.

The same feedback works in reverse. Reducing visceral fat lowers inflammatory cytokine production. Lower inflammation improves insulin sensitivity. Better insulin sensitivity reduces hyperinsulinaemia, slowing further fat accumulation. The system can shift toward a healthier equilibrium, and partial improvements across multiple pathways often produce synergistic benefit rather than simply additive effects. PREDIMED demonstrated this empirically: a Mediterranean-style dietary pattern produced higher rates of metabolic syndrome resolution than a control diet.[27] Once one loop starts moving in the right direction, the others tend to follow.

Reversibility has limits. Beta-cell function, once substantially lost, does not fully recover, and atherosclerotic plaque, once established, does not disappear. This is why earlier intervention produces larger and more durable improvements: there is simply more biology left to work with.

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The Bottom Line

Metabolic syndrome develops when the body’s capacity to safely manage sustained caloric excess is exceeded: visceral fat accumulates, becomes inflammatory, and sets in motion a cascade that reaches liver, muscle, vasculature, and pancreas at once. The five clinical criteria are downstream signals of that process, not its cause.

The drivers are biological and the accelerants environmental (ultra-processed foods, prolonged sitting, short sleep, chronic stress), and none of these is destiny. The same feedback loops that amplify dysfunction can work in reverse. Because these pathways are interconnected, improving sleep, activity, diet, and stress together tends to compound: partial gains across several systems meaningfully reduce long-term cardiovascular risk even when full reversal is not achievable.

Recognising the pattern earlier preserves more biological capacity than treating advanced disease later. Understanding the cause is what makes intervention possible.

Continue to Article 3: The Gut Microbiome and Heart Health → Article 3 examines an increasingly discussed contributor, the gut microbiome, and what current evidence does and does not support about its role in cardiovascular and metabolic health.

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Key Terms

Adipokines: Chemical messengers secreted by fat tissue that influence metabolism and inflammation throughout the body.

Endothelium: The single-cell lining of every blood vessel; endothelial dysfunction impairs nitric oxide signalling and often precedes clinically apparent cardiovascular disease by many years.

Hyperinsulinaemia: Chronically elevated insulin levels, initially compensatory for insulin resistance but also a driver of downstream syndrome features.

Insulin resistance: Reduced cellular responsiveness to insulin; higher insulin levels are required to maintain glucose control.

Leptin resistance: Impaired brain response to leptin signalling despite elevated leptin levels; contributes to impaired satiety in established metabolic syndrome.

Myokines: Signalling molecules produced by skeletal muscle during contraction; many have anti-inflammatory and insulin-sensitising effects.

Portal circulation: Blood supply carrying nutrients and signals from the gut and visceral fat directly to the liver before reaching the systemic circulation.

Visceral adipose tissue: Fat surrounding the abdominal organs; drains into the portal circulation; a strong independent predictor of metabolic and cardiovascular risk.

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References

1. Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation. 2007;116(1):39–48. https://doi.org/10.1161/CIRCULATIONAHA.106.675355
2. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement. Circulation. 2009;120(16):1640–1645. https://doi.org/10.1161/CIRCULATIONAHA.109.192644
3. Wang R, Liu J, Fang G, et al. Association between visceral adiposity index and cardiovascular disease: a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis. 2025;35(12):104216. https://doi.org/10.1016/j.numecd.2025.104216
4. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85–97. https://doi.org/10.1038/nri2921
5. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–1808. https://doi.org/10.1172/JCI19246
6. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793–1801. https://doi.org/10.1172/JCI29069
7. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860–867. https://doi.org/10.1038/nature05485
8. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction. Arterioscler Thromb Vasc Biol. 1999;19(4):972–978. https://doi.org/10.1161/01.ATV.19.4.972
9. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107. https://doi.org/10.1038/nri2925
10. Lillioja S, Mott DM, Spraul M, et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993;329(27):1988–1992. https://doi.org/10.1056/NEJM199312303292703
11. Martínez Steele E, Baraldi LG, Louzada ML, et al. Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study. BMJ Open. 2016;6(3):e009892. https://doi.org/10.1136/bmjopen-2015-009892
12. Hall KD, Ayuketah A, Brychta R, et al. Ultra-processed diets cause excess calorie intake and weight gain: an inpatient randomized controlled trial of ad libitum food intake. Cell Metab. 2019;30(1):67–77.e3. https://doi.org/10.1016/j.cmet.2019.05.008
13. Qu Y, Hu W, Huang J, et al. Ultra-processed food consumption and risk of cardiovascular events: a systematic review and dose-response meta-analysis. eClinicalMedicine. 2024;69:102484. https://doi.org/10.1016/j.eclinm.2024.102484
14. Lane MM, Gamage E, Du S, et al. Ultra-processed food exposure and adverse health outcomes: umbrella review of epidemiological meta-analyses. BMJ. 2024;384:e077310. https://doi.org/10.1136/bmj-2023-077310
15. Vadiveloo MK, Gardner CD, Bleich SN, et al. Ultraprocessed foods and their association with cardiometabolic health: evidence, gaps, and opportunities: a science advisory from the American Heart Association. Circulation. 2025;152:e245–e263. https://doi.org/10.1161/CIR.0000000000001365
16. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8(8):457–465. https://doi.org/10.1038/nrendo.2012.49
17. Healy GN, Wijndaele K, Dunstan DW, et al. Objectively measured sedentary time, physical activity, and metabolic risk: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Diabetes Care. 2008;31(2):369–371. https://doi.org/10.2337/dc07-1795
18. Young DR, Hivert MF, Alhassan S, et al. Sedentary behavior and cardiovascular morbidity and mortality: a science advisory from the American Heart Association. Circulation. 2016;134(13):e262–e279. https://doi.org/10.1161/CIR.0000000000000440
19. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435–1439. https://doi.org/10.1016/S0140-6736(99)01376-8
20. Spiegel K, Tasali E, Penev P, Van Cauter E. Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141(11):846–850. https://doi.org/10.7326/0003-4819-141-11-200412070-00008
21. Zuraikat FM, Laferrère B, Cheng B, et al. Chronic insufficient sleep in women impairs insulin sensitivity independent of adiposity changes: results of a randomized trial. Diabetes Care. 2024;47(1):117–125. https://doi.org/10.2337/dc23-1156
22. Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome. J Am Coll Cardiol. 2013;62(7):569–576. https://doi.org/10.1016/j.jacc.2013.05.045
23. Björntorp P. Do stress reactions cause abdominal obesity and comorbidities? Obes Rev. 2001;2(2):73–86. https://doi.org/10.1046/j.1467-789x.2001.00027.x
24. Chandola T, Brunner E, Marmot M. Chronic stress at work and the metabolic syndrome: prospective study. BMJ. 2006;332(7540):521–525. https://doi.org/10.1136/bmj.38693.435301.80
25. Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance: a population-based twin study. Diabetologia. 1999;42(2):139–145. https://doi.org/10.1007/s001250051131
26. Loos RJF, Yeo GSH. The genetics of obesity: from discovery to biology. Nat Rev Genet. 2022;23(2):120–133. https://doi.org/10.1038/s41576-021-00414-z
27. Babio N, Toledo E, Estruch R, et al. Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial. CMAJ. 2014;186(17):E649–E657. https://doi.org/10.1503/cmaj.140764

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