Metabolic Flexibility: A Valid Concept or a Catchy Term?

Jesse Oswald • June 5, 2024

Key Points

  • The body’s ability to rapidly and efficiently switch between oxidations of different energy substrates, namely fat and carbohydrates, depending on their availability, is known as metabolic flexibility.
  •  Long-term caloric excess and ectopic fat accumulation are central mechanisms of impaired metabolic flexibility.
  •  Insulin resistance is the link among a cluster of metabolic disturbances that are all characterized by impaired metabolic flexibility.
  •  Mitochondrial dysfunction is a principal component of impaired metabolic flexibility.
  •  Regular exercise and a healthy, low-calorie diet can significantly improve metabolic flexibility.
  •  RER fluctuations measured through breath analysis when alternating between fasted and fed states can be used as an index of metabolic flexibility.

 

Human physiology has evolved during dramatic fluctuations in energy supply and demand. Coping with these challenges has enabled the human body to manage energy metabolism for optimal substrate storage and utilization during either food surplus or shortage and of either rest or increased calorie burn. This ability to efficiently adjust metabolism to fluctuations in energy demand by rapidly and efficiently switching between oxidations of different energy substrates, namely fat and carbohydrates, depending on their availability, is known as metabolic flexibility. More specifically, metabolic flexibility is our body’s ability to switch from high levels of fat oxidation during fasted states to increased carbohydrate utilization during feeding states. The greater our ability to burn the food we consume instead of storing it, the more metabolically flexible we are.

 

Humans constantly cycle from fasting to postprandial (post-meal) conditions and vice versa. The primary purpose of this substrate shift is to move from catabolic (the metabolic process of breaking down fuels for energy production) to anabolic (the metabolic process of synthesizing molecules such as glycogen and triglycerides for energy storage) activities in which energy can be effectively stored in skeletal muscle, fat, and liver tissues.

 

Metabolic flexibility is not an ‘’on-off’’ phenomenon. It involves constant, tightly regulated adaptive responses of human metabolism to maintain energy homeostasis by matching fuel availability and demand to various conditions such as periodic fasting, varying meal composition, physical activity, and environmental fluctuations. However, nowadays, when the food supply overflows and there is a plethora of calorically dense processed foods combined with low levels of physical activity, metabolic flexibility is directly obstructed.

 

In this article, we will review the principle mechanisms that control metabolic flexibility, its implications for health, and the prominent role diet and exercise play in maintaining it.

 

Physiologic Mechanisms Leading to Metabolic Inflexibility

 

Healthy cells of metabolically active organs such as the liver, skeletal muscle, and fat tissue are metabolically flexible and communicate to organize the utilization of available fuels best. The inability to adapt to fuel availability may result in an abnormal mobilization and utilization of fat and glucose, leading to increased fatty acids and glucose concentration. After fat cells reach a threshold of calorie and lipid capacity, lipids accumulate in locations other than fat tissue, including skeletal muscle and the liver. This process, known as ectopic fat deposition, leads to lipotoxicity and, eventually, metabolic abnormalities and disrupts metabolic flexibility. Therefore, the previously healthy cells have now turned into dysfunctional cells.

 

Metabolic inflexibility is characterized by reduced skeletal muscle glucose transport, increased suppression of fat tissue lipolysis, reduced suppression of hepatic glucose production, and skeletal muscle mitochondrial dysfunction. All these defects result in increased glucose production by the liver, reduced glucose utilization for energy by the muscles, and decreased fat burn. At the core of these processes lies long-term caloric excess and ectopic fat accumulation. As a result, metabolic inflexibility and ectopic fat accumulation reinforce each other in a vicious cycle, causing and further cultivating metabolic dysfunction.

 

Metabolic Flexibility and its Association with Insulin Resistance

 

Impaired metabolic flexibility is associated with an increased risk of obesity and obesity-related pathologies, such as metabolic syndrome, type 2 diabetes, systemic inflammation, cardiovascular disease, and cancer. Simultaneously, obesity, especially central obesity, where fat accumulates around the abdomen, is the leading cause of insulin resistance. Insulin resistance is the inability of muscle, liver, and fat cells to respond to insulin, thus taking up and utilizing ingested carbohydrates for energy.

 

Insulin resistance is a vital component of the metabolically inflexible state, which is typically characterized by decreased fat oxidation during fasting and a reduced ability to upregulate carbohydrate oxidation during feeding. Therefore, the ingested carbohydrates are stored as fat in the fat tissues and other organs (ectopic fat).

 

Insulin resistance is also the predominant factor leading to type 2 diabetes and the link among a constellation of cardiometabolic risk factors known as metabolic syndrome, linking obesity, type 2 diabetes, and cardiovascular disease. Consequently, it’s becoming clear that not only Impaired metabolic flexibility is associated with an increased risk of insulin resistance but that insulin resistance itself deteriorates metabolic flexibility as well; hence why most individuals with obesity and/or type 2 diabetes are metabolically inflexible.

 

Metabolic syndrome is defined as having at least three components: visceral obesity in terms of elevated waist circumference, insulin resistance in terms of elevated fasting glucose, high blood pressure, elevated triglycerides, and/or low HDL-cholesterol. One of the hallmarks of metabolic syndrome is chronic systemic inflammation. Along with obesity and insulin resistance, systemic inflammation can trigger and propagate metabolic inflexibility. Thus, metabolic inflexibility, inflammation, obesity, and insulin resistance are part of a vicious cycle where the one trigger and reinforces the other. While impaired metabolic flexibility is strongly associated with insulin resistance, which of the two precedes is still unresolved.

 

Overall, metabolic health is defined as a comprehensive state of well-being, and metabolic flexibility is essential for metabolic health and the absence of metabolic diseases, such as the metabolic syndrome.

 

Mitochondrial Dysfunction: The Cause or the Consequence of Metabolic Inflexibility?

 

Mitochondria are dynamic intracellular organelles that play a foundational role in energy metabolism. When energy supply exceeds energy demand across the mitochondria (chronic caloric surplus), their oxidative capacity is reduced, predisposing to adverse health outcomes, such as the development of type 2 diabetes and obesity.

 

The concept of metabolic flexibility has particularly been associated with the mitochondria's function and places mitochondrial function at its core. Mitochondria are crucial in determining whole-body metabolic flexibility, and the deregulation of mitochondrial function underlies the onset of metabolic inflexibility. More specifically, mitochondrial dysfunction, in terms oflow skeletal muscle mitochondrial capacity, function, and/or density, is associated with reduced resting lipid oxidation and, therefore, increased muscle lipid accumulation (ectopic fat) and insulin resistance.

 

Although the hypothesis that such mitochondrial abnormalities may be a primary cause of metabolic inflexibility has been raised, definite conclusions regarding the causal relationship cannot be drawn based on current evidence. However, a substantial body of evidence supports impaired mitochondrial adaptation as a principal component of systemic metabolic inflexibility, particularly in conditions related to insulin resistance, such as metabolic syndrome. Therefore, the relationship between insulin resistance and altered mitochondrial function seems to be bidirectional and mutually amplifying.

 

Metabolic Flexibility and its Relation to Physical Activity and Diet

 

Several studies have highlighted the positive relationship between sedentary behaviours, such as time spent sitting, and the risk of developing obesity, type 2 diabetes, and cardiovascular disease. Indeed, regular physical exercise is a key determinant of metabolic flexibility, favouring metabolic and cardiovascular health while preventing weight gain and its related metabolic abnormalities. Exercise training increases metabolic flexibility by reducing insulin resistance and increasing muscle lipid oxidation.

 

Therefore, it’s becoming clear that exercise profoundly affects metabolic flexibility. This effect is also mediated by the impact of exercise on the mitochondria. Current evidence shows that exercise-trained skeletal muscles, especially of endurance athletes, present increased skeletal muscle mitochondrial biogenesis and have higher mitochondrial content, capacity, and function. In other words, exercise-enhanced mitochondrial performance is related to better metabolic flexibility. In contrast, skeletal muscle from individuals with obesity and insulin resistance is metabolically inflexible compared with skeletal muscle from healthy individuals.

 

Besides physical activity, a chronic caloric surplus is another major factor impairing mitochondrial function and inducing metabolic flexibility. Therefore, weight loss through a suitably applied caloric deficit is crucial in restoring metabolic flexibility and is the most common intervention for obesity and obesity-related metabolic comorbidities.

 

Physical activity, especially aerobic exercise, is an effective way to improve metabolic flexibility. Combined with a proper nutrition regime that will not be characterized by overconsumption of calories and nutrients from highly processed caloric-dense foods that promote weight gain, thus dysregulation of metabolic health,it can comprise the best strategy to restore metabolic flexibility.

 

Can breath Analysis be Utilized as an Index of Metabolic Flexibility?

 

Metabolic flexibility as individuals alternate between feeding and fasting can be assessed through changes in the respiratory exchange ratio (RER), calculated from the VCO2-to-VO2 ratio measured by breath analysis (AKA indirect calorimetry). RER is an index of the proportion of carbohydrates and fat being oxidized for energy.

 

RER typically fluctuates between 0.7 and 1.0 in humans, depending on the fuel being oxidized. When fat or glucose is the unique energy source, the RER is 0.7 or 1.00, respectively. In fasted conditions, typically, RER is about 0.80 in subjects fed with mixed diets, while values lower than 0.75 are observed in individuals fed with low-carbohydrate diets (<30% of energy from carbohydrates). Individuals with negative energy balance or fed high-fat diets (>50% of energy from fat) tend to have even lower fasting RER values. However,in a state of increased visceral fat (central obesity) and insulin resistance, there is a higher preference for glucose relative to fat as an energy source in the fasting state (high fasting RER).

 

The extent to which RER increases from fasting to feeding conditions has been considered an index of metabolic flexibility. An impaired drop in RER during an overnight fast (high fasting RER→glucose oxidation predominance and inability to switch to fat oxidation), as well as an impaired rise in RER in response to feeding (baseline RER of ≈0.85, which fails to increase further), indicates a metabolically inflexible state. Several studies suggestthis is the case for obese insulin-resistant and type 2 diabetic subjects.

 

However, indirect calorimetry should be used with caution and critical thinking to measure metabolic flexibility. Someone should always consider a subject’s energy balance and dietary macronutrient composition while interpreting the results since those factors affect the RER.

 

In summary, metabolic flexibility is not only a valid term regarding metabolic health. Still, it may actually underlie the epidemic changes in metabolic disease that affect all demographic groups and burden healthcare systems. It may also be an early condition that, if timely detected and appropriately handled, could prevent the onset of several serious metabolic disturbances, such as type 2 diabetes and cardiovascular disease.

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Predicting Medical Costs with VO2max

By Jesse Oswald • January 20, 2025
Highlights Healthcare expenses are skyrocketing, with consumers and employers facing the significant brunt. Identifying those likely to get sick is critical as our resource-strapped healthcare system should focus on those likely to become the most significant burden to the system. VO2 max is a crucial longevity indicator that can also accurately predict healthcare expenses. The rampant chronic disease epidemic and the resulting surge in medical expenses is one of the most dire problems of modern societies, probably only second to climate change. Healthcare inflation is on a meteoric rise, and for those with limited or no healthcare coverage, a medical emergency is the equivalent of personal bankruptcy. A dire problem for employers In the US, employers and consumers who face rising health insurance premiums and astronomical out-of-pocket medical expenses feel the brunt of rising healthcare costs. Such is the problem that even large, well-capitalized corporations choose to send employees overseas for specific medical procedures since the cost of traveling and treatment in a foreign country is lower than the cost of care in the US. Another startling example is the infamous "northern caravan," a term that describes people with diabetes in the northern states who travel to Canada to secure their insulin supply. According to McKinsey , a survey conducted among over 300 employers highlighted that the average increase in the cost of health benefits over the past three years has been within the range of 6 to 7 percent. This survey also indicated that any rate increases exceeding 4 to 5 percent were deemed unsustainable. Interestingly, 95 percent of the surveyed employers expressed willingness to contemplate reducing benefits if costs surged by 4 percent or more. The primary cost-control measures that these employers indicated they might explore included elevating the portion of premium costs covered by employees and a potential transition to high-deductible health plans. Why is Breath Analysis relevant? Vis-a-vis this problem, the early and accurate estimation of who will get sick and how much they will cost is as critical as the treatment itself. The reason is that no other method of accurately identifying at-risk populations exists; it helps focus our scarce prevention resources and attention on those most in need. Breath analysis, AKA VO2max or metabolic testing, is an assessment that reveals two key biomarkers that provide significant predictive value for one's likelihood of developing costly chronic conditions. These two biomarkers are VO2max and the Respiratory Exchange Ratio. In this article, we will dive into VO2max to understand why it's a critical reflection of our overall health and, consequently, a window into our future healthcare spend. What is VO2max? Let's start with the basics. What is VO2max? VO2 max is the maximum amount of oxygen the human body can absorb. It is measured in terms of milliliters of oxygen consumed per kilogram of body weight. The below formula below indicates how VO2max is calculated: The numerator indicates the volume of oxygen your heart, lungs, and cells can absorb, expressed in milliliters per minute. The denominator indicates the weight of the individual represented in kilograms. 
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Dietary Fat: An Essential Dietary Component Rather than the root of all Nutritional Health Issues

By Jesse Oswald • January 13, 2025
Key points A total fat intake between 20-35% ensures sufficient intake of essential fatty acids and fat-soluble vitamins Omega-6 PUFAs are primarily found in vegetable oils, while omega-3 PUFAs are primarily found in fatty fish and fish oils Both omega-3 PUFAs and MUFAs have established benefits for cardiovascular disease TFAs are the only dietary lipids that have a strong positive relationship with cardiovascular disease Omega-3 PUFA supplementation increases the beneficial bacteria of the human microbiome Over the last three decades, there has been a great revolution against fat due to its suspected association with several nutritional health issues, especially cardiovascular disease. There was a tremendous amount of evidence that indicated dietary cholesterol and saturated fat as the main culprits of cardiovascular disease, thus morbidity and mortality. It was when all the low-fat and no-fat dairy products started to launch, promising even complete substitution of the cholesterol-lowering heart medication if these products were exclusively consumed. Let’s start from the beginning. Dietary fat intake can vary significantly and still meet energy and nutrient needs. International guidelines suggest a total fat intake between 20% and 35% of the daily caloric consumption. This range ensures sufficient intake of essential fatty acids and fat-soluble vitamins. Not only does the quantity of the ingested fat matter, but most importantly, its quality. Some dietary fats have beneficial effects, with a significant role in maintaining good health, while others may threaten it. Which are, after all, the dietary fats? Dietary fats is a rather heterogeneous group of organic compounds, including four main types of fat, which are elaborately described in the following sections of this article. Polyunsaturated fatty acids (PUFAs) Polyunsaturated fatty acids (PUFAs) have two or more carbon-carbon double bonds. Omega-6 PUFAs and omega-3 PUFAs are the main types of PUFAs and are classified according to the location of the first unsaturated bond (sixth and third carbon atom, respectively). Alpha-Linolenic acid (ALA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), and eicosapentaenoic acid (EPA) are the most important omega-3 PUFAs. ALA is an essential fatty acid that can only be obtained from diet and can be converted into EPA and then to DHA, but the rate of this conversion is finite, approximately 7.0%–21% for EPA and 0.01%–1% for DHA. In the same way, the most important omega-6 PUFAs are linoleic acid (LA) and arachidonic acid (ARA). LA is an essential fatty acid that, in order to give rise to ARA, needs to be ingested through the diet as the human body cannot synthesize it. The recommended intake for total PUFA ranges between 5% and 10% of the total energy intake, while a total omega-3 PUFA intake of 0.5%–2% and a total omega-6 PUFA intake of 2.5%-5% is suggested. A dietary ratio of omega−6/omega−3 PUFA is recommended to be 1:1–2:1 to balance their competing roles and achieve health benefits. Omega-6 and omega-3 PUFAs Omega-6 PUFAs, in the form of LA, are plentiful in most crop seeds and vegetable oils, such as canola, soybean, corn, and sunflower oils. In contrast to omega-6 PUFAs, omega-3 PUFAs are obtained from a limited range of dietary sources. Flax, chia, and perilla seeds are rich in ALA, with significant amounts also detected in green leafy vegetables. The consumption of fatty fish, such as salmon, sardines, tuna, trout, and herring, provides high amounts of EPA and DHA. Besides fish and their oils, small amounts of omega-3 PUFAs are also detected in red meat like beef, lamb, and mutton. All the above dietary sources provide EPA, DPA, DHA, LA, and ARA in different amounts, and their intake is necessary for normal physiological function. PUFAs play a critical role in many chronic diseases, affecting human cells by regulating inflammation, immune response, and angiogenesis. Omega-3 PUFAs’ role against hypertriglyceridemia has been clarified, and research indicates that systematically consuming oily fish can contribute to general heart protection. Supplementation with omega-3 PUFAs could potentially lower the risk of several cardiovascular outcomes, but the evidence is stronger for individuals with established coronary heart disease. Moreover, adequate EPA and DHA levels are necessary for brain anatomy, metabolism, and function. Although the mechanisms underlying omega-3 PUFAs' cardioprotective effects are still poorly understood, several studies have been conducted in this direction. Unfortunately, that does not hold true for their omega-6 counterparts, for which controversial emerging data tend to show anti-inflammatory behavior that needs to be further studied. Monounsaturated fatty acids (MUFAs) In contrast to PUFAs, monounsaturated fatty acids (MUFAs) are easily produced by the liver in response to the ingestion of carbohydrates. The main MUFA is oleic acid, found in plant sources, such as olive oil, olives, avocado, nuts, and seeds, while minimal amounts are also present in meat, eggs, and dairy products. Specific guidelines around MUFAs’ dietary consumption do not exist. Therefore, MUFAs are recommended to cover the remaining fat intake requirements to reach the total daily fat intake goal. A growing body of research shows that dietary MUFAs reduce or prevent the risk of metabolic syndrome, cardiovascular disease (CVD), and hypertension by positively affecting insulin sensitivity, blood lipid levels, and blood pressure, respectively. Moreover, olive oil contains several bioactive substances, possessing anti-tumor, anti-inflammatory, and antioxidant qualities. According to a meta-analysis, consuming olive oil was linked to a lower risk of developing any sort of cancer, especially breast cancer and cancer of the digestive system. Another study found that an isocaloric replacement of 5% of the energy from saturated fatty acids (SFAs) with plant MUFAs led to an 11% drop in cancer mortality over a 16-year follow-up period. Therefore, including MUFAs in the everyday diet offers multifaceted benefits in chronic disease prevention and management, including cancer and general health promotion.  Saturated fatty acids (SFAs) Saturated fatty acids (SFAs) form a heterogeneous group of fatty acids that contain only carbon-to-carbon single bonds. Whole-fat dairy, (unprocessed) red meat, milk chocolate, coconut, and palm kernel oil are all SFA-rich foods. These fatty acids have distinct physical and chemical profiles and varying effects on serum lipids and lipoproteins. Stearic, palmitic, myristic, and lauric acids are the principal SFAs found in most natural human diets. Dietary practice and guidelines recommend limiting SFA intake to <10% of the total energy (E%), while the American Heart Association suggests an even lower intake of <7 E% because total saturated fat consumption and LDL-C levels are positively correlated. However, the role of SFAs in CVDs is quite complex, and the evidence is heterogeneous. In a recent study with a 10.6-year follow-up period, which included 195,658 participants, there was no proof that consuming SFAs was linked to developing CVD while replacing saturated fat with polyunsaturated fat was linked to an increased risk of CVD. Moreover, according to 6 systematic reviews and meta-analyses, cardiovascular outcomes and total mortality were not significantly impacted by substituting saturated fat with polyunsaturated fat. Even if these analyses were to be challenged, due to heterogenous evidence, the possible reduction in CVD risk associated with replacing SFAs with PUFAs in several studies may not necessarily be an outcome of SFAs’ negative effect but rather a potential positive benefit of PUFAs. Regarding SFAs' effect on different types of cancers, associations of their intake with an increased risk of prostate and breast cancer have been indicated. Conversely, a meta-analysis showed no link between SFA intake and a higher risk of colon cancer; similarly, consuming MUFAs, PUFAs, or total fat did not affect colon cancer risk. Hence, the role of SFA consumption in preventing, promoting, or having a neutral role in serious chronic diseases has not been fully elucidated yet. Trans fatty acids (TFAs) Trans fatty acids (TFAs) are created industrially by partially hydrogenating liquid plant oils or can be naturally derived from ruminant-based meat and dairy products. TFAs are highly found in commercial baked goods, biscuits, cakes, fried foods, etc. Guidelines regarding TFAs are stringent and limit TFA intake to <1% of energy or as low as possible. In 2015, the US Food and Drug Administration declared that industrial TFAs are no longer generally recognized as safe and should be eliminated from the food supply as their consumption is strongly linked to various CVD risk factors. Specifically, TFA intake raises triglycerides and increases inflammation, endothelial dysfunction, and hepatic fat synthesis, leading to a significantly increased risk of coronary heart disease (CHD). A meta-analysis suggested that increased TFA intake led to an increase in total and LDL-cholesterol and a decrease in HDL-cholesterol concentrations. Data also indicates that TFAs may influence carcinogenesis through inflammatory pathways, but the reported data are debatable. A recent study investigated the effects of all types of dietary fat intake on CVD risk. While PUFA, MUFA, and SFA intake were not linked to higher CVD risk, dietary TFA intake showed a strong association with CVD risk. Analysis indicated PUFA intake and CVD risk were inversely correlated, and the relative risk of CVD was reduced by 5% in studies with a 10-year follow-up. Dietary lipids and the human microbiome Dietary lipids also affect human microbiota composition. Studies have identified a close association between the human microbiome and metabolic diseases, including obesity and type 2 diabetes. Diets with a high omega-6 PUFA, SFA, and TFA intake increase the amount of many detrimental bacteria in the microbiome and reduce the amount of the beneficial ones, altering the microbiota composition and inducing inflammation via the secretion of pro-inflammatory cytokines. These bacteria may disrupt the gut barrier function, allowing lipopolysaccharides (LPS) translocation, which are bacterial toxins. This condition is linked to metabolic perturbations such as dyslipidemia, insulin resistance, non-alcoholic fatty liver disease (NAFLD), and CVD. On the contrary, omega-3 PUFA (EPA and DHA) supplementation increases beneficial bacteria and limits harmful ones, enhancing intestinal barrier functioning and preventing LPS translocation and its implications. Omega-3 PUFA supplementation has also been studied as a means of mental health disorders management, but the evidence is still controversial. A possible protective impact of fish consumption on depression has been suggested by various studies, as well as a possible protective effect of dietary PUFAs on moderate cognitive impairment. A recent review of meta-analyses indicated that omega-3 PUFA supplementation might have potential value in mental health disorders, but data credibility is still weak. Dietary lipids and obesity Last but not least, obesity and its management is another field that dietary lipids intake seems to impact with their mechanisms. A diet high in PUFA has been shown to lower the total mass of subcutaneous white adipose tissue (the predominant fat type in human bodies), reduce blood lipid levels, and improve insulin sensitivity. In a study comparing PUFA and MUFA isocaloric intake, PUFA was more advantageous and lowered visceral adiposity in patients with central obesity. By stimulating brown adipose tissue, which aids energy expenditure through its elevated thermogenic activity, omega-3 PUFAs seem to elicit these positive effects in fat tissue, thus being useful in preventing and/or managing obesity. Another related study compared PUFA to SFA overfeeding in dietary surplus conditions that aimed to increase weight by 3%. While SFA overfeeding led to weight gain, primarily through the expansion of the visceral adipose tissue, PUFA overfeeding also led to weight gain, but because of a greater expansion of lean tissue mass. To sum up, dietary fats are an essential part of the human diet with many important physiologic functions, including cell function, hormone production, energy, and nutrient absorption. Moreover, dietary fat consumption is associated with positive outcomes in regard to cardiovascular disease, metabolic syndrome, cancer, and depression. Therefore, there is no reason to demonize this valuable dietary component, incriminating it for irrelevant adverse health outcomes, primarily weight loss failure and obesity. References 1. Astrup A, Magkos F, Bier DM, Brenna JT, de Oliveira Otto MC, Hill JO, King JC, Mente A, Ordovas JM, Volek JS, Yusuf S, Krauss RM. Saturated fats and health: A reassessment and proposal for food-based recommendations: JACC State-of-the-Art review. J Am Coll Cardiol. 2020;76(7):844-857. DOI: 10.1016/j.jacc.2020.05.077 2. Bojková B, Winklewski PJ, Wszedybyl-Winlewska M. Dietary fat and cancer-Which is good, which is bad, and the body of evidence. Int J Mol Sci. 2020;21(11):4114. DOI: 10.3390/ijms21114114 3. Custers, Emma EM, Kiliaan, Amanda J. Dietary lipids from body to brain. Prog Lipid Res. 2022;85:101144. DOI: 10.1016/j.plipres.2021.101144 4. de Souza RJ, Mente A, Maroleanu A, Cozma AI, Ha V, Kishibe T, Uleryk E, Budylowski P, Schünemann H, Beyene J, Anand SS. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ. 2015;351:h3978. DOI: 10.1136/bmj.h3978 5. Gao X, Su X, Han X, Wen X, Cheng C, Zhang S, Li W, Cai J, Zheng L, Ma J, Liao M, Ni W, Liu T, Liu D, Ma W, Han S, Zhu S, Ye Y, Zeng F-F. Unsaturated fatty acids in mental disorders: An umbrella review of meta-analyses. Adv Nutr. 2022;13(6):2217-2236. DOI: 10.1093/advances/nmac084 6. Liu AG, Ford NA, Hu FB, Zelman KM, Mozaffarian D, Kris-Etherton PM. A healthy approach to dietary fats: understanding the science and taking action to reduce consumer confusion. Nutr J. 2017;16(1):53. DOI: 10.1186/s12937-017-0271-4 7. Poli A, Agostoni C, Visioli F. Dietary fatty acids and inflammation: Focus on the n-6 series. Int J Mol Sci. 2023;24(5):4567. DOI: 10.3390/ijms24054567 8. Saini RK, Keum Y-S. Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance-A review. Life Sci. 2018;203:255-267. DOI: 10.1016/j.lfs.2018.04.049 9. Saini RK, Prasad P, Sreedhar RV, Naidu KA, Shang X, Keum Y-S. Omega-3 polyunsaturated fatty acids (PUFAS): Emerging plant and microbial sources, oxidative stability, bioavailability, and health benefits-A review. Antioxidants (Basel). 2021;10(10):1627. DOI: 10.3390/antiox10101627 10. Zhao M, Chiriboga D, Olendzki B, Xie B, Li Y, McGonigal LJ, Maldonado-Contreras A, Ma Y. Substantial increase in compliance with saturated fatty acid intake recommendations after one year following the American Heart Association diet. Nutrients. 2018;10(10):1486. DOI: 10.3390/nu10101486 11. Zhu Y, Bo Y, Liu Y. Dietary total fat, fatty acids intake, and risk of cardiovascular disease: a dose-response meta-analysis of cohort studies. Lipids Health Dis. 2019;18:91. DOI: 10.1186/s12944-019-1035-2
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