Image copyright 2016 New York Times. Included under the provisions of fair use under U.S. copyright law.

In 2013 the American Medical Association declared obesity a complex, chronic disease requiring medical attention. The intention behind this move was to require physicians to start treating obesity and require insurances to pay for treatment and prevention. Hopefully, giving health care providers and insurances a nudge to treat obesity would reduce the prevalence of costly diseases such as type 2 diabetes and cardiovascular disease.

The backlash was instantaneous.

For starters the AMA House of Delegates overrode a recommendation made by the an AMA expert panel. In their statement the experts cautioned that a better diagnostic criterium for obesity would need to be developed given the limitations of the BMI. Despite the BMI shortcomings the expert panel still preferred to classify obesity a condition or disorder, but was overruled by the house of delegates.

While part of the medical community applauded the decision others cautioned that this move would have rather detrimental affects. Treatment of a disease tends to focus on pricey drugs, medical technology, surgical procedures and expensive clinic visits instead of addressing the root problems of the obesity pandemic. Given the millions of affected Americans some were concerned that the cost of treatment would be staggering.

Others pointed out that a disease designation would move the blame to the individual and would lead to increased weight discrimination. There was also concern that people would be released from personal responsibility and somebody else—the government, medical establishment—would be in charge.

Years later, the uproar has subsided, but different camps are still arguing about how to approach obesity. Physicians and other medical personal still haven’t learned how to address weight in the examination room and weight discrimination is rampant in the medical system. On the other hand some health care providers ignore the physiological facts (for example the “Healthy at Every Size” movement) and focus mostly on the psychological arguments. Disease designation or not, health care providers need to understand the connection between obesity and chronic diseases and need to be trained to address weight in a health care setting in a constructive way.

During this first module you will learn about the connection between obesity, systemic chronic inflammation (SCI) and chronic disease. Once you have a solid understanding of this interaction we will explore how lifestyle decisions at every stage of life can increase or decrease the risk for obesity and chronic diseases, and ultimately determine the long-term quality of life.

Before you dive into the next chapters you should review some terminology and basic facts regarding body composition. The following review slide summarizes facts about adipose tissue, BMI, the difference between the two, and how both are evaluated.

Two more concepts need review so you can fully understand the chapter:

There are three types of adipose tissue. White adipose tissue (WAT) looks white because it is build from adipocytes that are filled with a large storage bubble of triglycerides. The few mitochondria and nucleus are squished to the side of the cell. The size of the fat bubble can increase or shrink depending on the energy status. If the energy balance is positive triglycerides are stored in the adipocyte, if the energy balance is negative triglycerides are mobilized.

Brown adipose tissue (BAT) is located in specific areas of the body, for example between the shoulder blades (scapulas). Infants have large amounts of BAT to help maintain body temperature. Adults have little BAT left, but this can vary from person to person. BAT looks brown because it has small dispersed fat droplets and many mitochondria. In BAT the electron transport chain is uncoupled. This means that energy is produced in form of heat instead of ATP.

Beige adipose tissue resides within the white adipose tissue. Beige adipocytes look and function like white adipocytes until they are activated by cold-exposure or exercise. Under exposure an uncoupling protein (UPC1) is synthesized and the electron transport chain is producing heat instead of ATP. After the exposure the beige adipocytes can go back to being white adipocytes.

Later in this chapter and in the next chapter about type-2 diabetes it will be important to understand where the free fatty acids are coming from. When we are in a positive energy balance the surplus carbohydrates and amino acids are converted into triglycerides in the liver. Food triglycerides do not need to be converted. The surplus energy in form of triglycerides is transported to the adipose tissue. There are two transport routes. Triglycerides with long-chain fatty acids are transported by chylomicrons directly from the small intenstine to the adipose tissue. Secondly, the liver packs surplus triglycerides into VLDL (very low density lipoproteins). When chylomicrons and VLDL arrives at the adipose tissue the enzyme lipoprotein lipase located in the blood vessel wall splitts triglycerides into fatty acids and glycerol. Fatty acids and glycerol diffuse into the adipocyte and are reassembled into triglycerides for storage.

If we are in a negative energy balance the adipose tissue releases glycerol and free fatty acids directly into the blood circulation. The fatty acids travel to the heart and skeletal muscles as well as the liver to undergo beta-oxidation. Glycerol travels to the liver to form glucose in the gluconeogenesis pathway.

Can You Be Healthy At Every Size?

At a very basic level obesity is having too much body fat. The question is if this is good or bad? If you believe the media then people can be healthy at any weight. This statement is too simplistic though. While some overweight and obese people—10 to 30 %—do not have any obvious health problems, we know that obesity and to a lesser degree overweight increases the risk for non-communicable diseases such as cardiovascular disease (CVD), hypertension, type 2 diabetes (T2D), some cancers, non-alcoholic fatty liver disease, osteoarthritis or rheumatoid arthritis. Obesity also affects reproductive health and there is newer research showing that the risk for dementia is higher in people with obesity.

When we talk about obesity it is important to keep in mind that not everybody who is obese will develop those diseases. But, we need to separate personal risk and public health impact. Even if only a small fraction of the 70 % of Americans who are overweight and obese develop one or more non-communicable diseases it becomes a public health issue. Obesity is a major contributor to disability, medical costs, lost years of life and generates a huge societal cost.

The scientific community has researched factors contributing to obesity for a long time. Based on this initial evidence obesity was seen as a personal responsibility. Overeating and insufficient physical activity were cited as the main risk factors. During the last decades the research showed that this was far too simplistic (see chapter 5).

Weight Gain and Obesity Are Complex, Multi-Factorial Health Conditions

Based on this extensive research we know that obesity is not just an issue of lacking will power. It became increasingly clear that weight gain and obesity are very complex multi-factorial health conditions. Multiple factors promote weight gain and make weight maintenance even after the weight is lost very difficult.

Genetic predisposition determines where body fat is stored and how much is stored. Some people have a more efficient metabolism and respond to temporary overeating by putting on weight (“thrifty metabolism”). During famines, which were common not too long ago, this genetic feature was a plus when it came to survival. Today, in an environment of constant abundance, a thrifty metabolism makes those people more prone for weight gain and ultimately chronic diseases.

Others have a genetic predisposition to store fat predominantly around the midsection. This is called central obesity. If the central adipose tissue is located around the organs inside the abdominal cavity it is called visceral obesity. Central obesity is more common in men and that is why it is also named android obesity. Gynoid obesity is more common in women with increased fat deposits around hips and thighs.

With age fat stores tend to increase and storage tends to shift toward central and visceral obesity in both genetic types. A genetic predisposition and advancing age do not necessarily mean that a person will become automatically obese. It will require a lot of work, knowledge and skills to maintain a healthy weight.

Eating a diet with a high energy density—high in added sugar, high in fat, low in fiber-rich plant food—makes it more likely that a person becomes overweight or obese. Research shows that people eating a plant-heavy diet, limiting fatty and sugary foods and reducing the consumption of ultra-processed foods maintain a healthy weight throughout life much easier.

Avoiding a sedentary lifestyle, increasing physical activity and regular exercise, support the nutrition side. While exercise, unless it is very extensive and intense, is often not sufficient to maintain a healthy weight, exercise and physical activity contribute to improved health and reduce the risk of non-communicable diseases at any weight.

The food environment impacts weight as well. In the US living a healthy lifestyle is an uphill battle at best and for underserved groups often not accessible. Availability of healthy foods at a reasonable prize, developing food preparation skills, and city planning that increases access to healthy foods and promotes physical activity would make it easier to choose healthy options.

Learned health behaviors such as how we choose food and how we eat our meals determine the trajectory of our weight.

Psychological factors such as a negative body perception, stress and emotional distress can be connected to emotional eating and lead to a steady weight increase.

Newer research also shows that other lifestyle choices promote slow weight gain. Lack of sleep might not be a main factor for weight gain but can contribute.

Based on this extensive knowledge health professionals developed health policies, recommendations, and intervention programs. Of course scientists researched the success of these programs and the results are rather disappointing. Health policies and intervention programs are frustratingly ineffective. Even if people lost a good amount of weight, the weight came back soon with a vengeance. Only 5 % of people losing weight will maintain the new lower weight long-term. Despite what the media says, that holds true for the popular keto and low-carb diets as well.

What is going on? Did those scientists miss anything?

Adipose Tissue Is Not Just an Energy Store But an Endocrine Organ

So far, we established that eat less, exercise more is too simplistic to explain why people fail to maintain a healthy weight. People gain weight over a lifetime as a combination of personal, environmental and learned behaviors. The question is now why health interventions and nutrition policy are not able to turn the obesity epidemic around by addressing these factors.

You will understand why when you understand the function of the adipose tissue and the metabolic changes that happen progressively during weight gain.

Before the early 1990s we thought that white adipose tissue, or WAT for short, is composed from adipocytes and blood vessels. We thought that chylomicrons deposit part of the fat after a meal directly into the adipose tissue. In addition, very-low density lipoproteins (VLDL) transport triglycerides produced by the liver from surplus carbohydrates, amino acids or alcohol to the WAT.

There, lipoprotein lipase in the blood vessel wall is activated and hydrolyzes the triglycerides. The fatty acids can now pass into the adipocyte where they are rapidly re-esterified into triglycerides and stored. When energy is needed the triglycerides in the adipose tissue undergo lipolysis and fatty acids are released directly into the blood circulation and are taken up by cells in need for energy.

While this is still correct, our knowledge about adipose tissue has expanded immensely since then.

The figure on the left shows the cells of the adipose tissue. While adipocytes, the specialized cells storing triglycerides, account for most of the white adipose tissue volume, they make up only around 50 % of the cells.  In addition to the fat storing adipocytes, adipose tissue also contains a plethora of other cells such as immune cells, fibroblasts stabilizing the adipose tissue, vascular cells connecting the adipose tissue to the blood circulation and precursor cells to grow new adipocytes. Adipocytes do not just store fat but also communicate with other body tissues by synthesizing and secreting messenger molecules regulating blood pressure, triggering an immune system response, modifying glucose and lipid metabolism, regulating reproduction, maintaining bone homeostasis, regulation vascular growth and many more (infographic above, right).

Many of those messenger chemicals are also produced by other endocrine tissues and they collaborate with the adipose tissue to regulate the bodily functions mentioned above.

The adipose tissue also produces and secretes chemicals that are only secreted by the adipose tissue. These are called the adipokines. Adipokines are small peptides that are secreted into the vascular system and message the status of the adipose tissue to other tissues and organs. Targets include the brain, liver, pancreas, immune system, vasculature, muscle, and many other tissues. It is estimated that over 600 adipokines exist but they are by far not all researched. The best researched adipokines are leptin, adiponectin and to a lesser degree resistin.

Since this line of research is fairly new, we need to keep in mind that research is ongoing. While we lack understanding how those secreted chemicals work together, we do understand that expanding adipose tissue changes the secretion of those messenger molecules profoundly. As a consequence increasing fat mass changes how the metabolism works.

There is no way to address all those messenger molecules in this chapter. Instead we will focus on several molecules that are important to understand the connection between obesity and chronic diseases. You will study the basics for the adipokines leptin, adiponectin and resistin as well as the hormones estrogen and cortisol, and the proinflammatory cytokines.

The adipokine leptin is a small protein that signals the energy availability of the adipose tissue to other organs. Primarily, leptin signals to the brain regulating satiety, but the same signals are also used to fine tune fertility, the inflammatory state of our metabolism and many more.

As adipose tissue grows—let’s say during the holiday season in November and December—it releases more leptin into the blood stream. Receptors in the brain measure the increasing amount of leptin and signal fullness. When we work off those pesky pounds later in January leptin blood levels fall with shrinking adipose tissues and that makes us hungry.

If we don’t lose the weight and instead steadily increase adipose tissue, leptin blood levels keep increasing as well. Once leptin blood levels are persistently high you would think that the body keeps signaling fullness, but now a counter regulation kicks in. The body becomes leptin resistant. This means since there is so much leptin in the blood the body produces less leptin receptors in the target organs. Leptin becomes now ineffective to signal energy status and satiety. In leptin resistance falling leptin blood levels during weight loss are registered by the confused brain as a starvation period and severe hunger will set in.

Adiponectin: While leptin secretion increases with growing adipose tissue, adiponectin secretion declines with growing adipose tissue. Adiponectin is less researched than leptin. So far we know that adiponectin is involved in the regulation of blood glucose levels, fatty acid breakdown and regulation of the immune response.

In lean people adiponectin circulates in high amounts and seems to have a protective effect against insulin resistance. The primary mechanisms by which adiponectin enhances insulin sensitivity appears to be through increased fatty acid oxidation and inhibition of hepatic glucose production. The anti-inflammatory properties of adiponectin reduce atherosclerotic processes in the blood vessels.

Cytokines—note that cytokines do not belong to the group of adipokines—are small messenger proteins and part of the cellular immune response. Cytokines can be proinflammatory (activating the iimmune response) or antiinflammatory (dampening the immune response). Proinflammatory cytokines are secreted by many cell types to signal an inflammatory state. In obesity adipocytes are able to produce proinflammatory cytokines and the amount produced is proportional to the amount of adipocytes.

Cytokines attach to corresponding receptors of target cells and modulate the metabolism of the target cell. That way cytokines coordinate the immune response between cells in the same tissue, but also the immune response between cells of different tissues.This altered regulation has impact aside of the immune response. In insulin sensitive cells such as muscles increased amounts of cytokines decrease insulin sensitivity.

I would like to touch on two more secretory adipose tissue functions you will need to keep in mind for the fertility, type 2 diabetes and hypertension chapter.

Cortisol the main stress hormone in the body is involved in the regulation of glucose metabolism. Higher blood cortisol levels result in higher blood glucose levels. In a stressful situation more available glucose means more readily available energy. Originally, this mechanism helped the muscles react fast during the fight-or-flight response. Adipose tissue does not produce cortisol directly, but has an enzyme that converts the pre-cursor cortisone into cortisol. Therefore more adipose tissue results in higher cortisol blood levels which in turn maintain higher blood glucose concentration.

Adipose tissue contains an enzyme called aromatase that converts androgens, the male sex hormones—women have also low amounts—into estrogen the main female sex hormone. In consequence, estrogen blood concentrations will rise with increasing adipose tissue in men and women. Keep this in the back of your mind until we talk about fertility and pregnancy.

RAS (renin–angiotensin system): We will get back to this later when we talk about obesity induced hypertension. Scientists think that adipocytes are able to secrete angiotensinogen one starting point of the blood pressure regulation. Adipose tissue also has high levels of the enzyme ACE. One of the function of ACE is to convert angiotensin I into angiotensin II. This mechanism can lead to increased blood pressure as adipose tissue growths.

Obesity Increases Systemic Chronic Inflammation (SCI)

Everybody talks about low-grade inflammation. Blogs and webpages warn of inflammation causing foods, recommend inflammation reducing diets, and peddle inflammation-reducing supplements. What is it?

When white adipocytes becomes very large—above capacity—they will start leaking free fatty acids (FFAs) into the surrounding adipose tissue. Since FFAs can freely pass through cell walls they will reach macrophages embedded in the adipose tissue. At the same time super large adipocytes can become hypoxic and are more likely to undergo cell death (apoptosis).

Leaking fatty acids and dead cells shouldn’t be in a well functioning adipose tissue and this prompts an innate immune reaction: The macrophages, embedded in the adipose tissue, secrete pro-inflammatory cytokines into the interstitial space between adipocytes. The cytokines start diffusing in the adipose tissue and bind to receptors on the adipocyte surface. This signals an inflammatory state to other adipocytes.

This inflammatory signal changes adipocyte metabolism and turns adipocytes into what is called an inflammatory phenotype. This means that the adipocytes start to produce proinflammatory cytokines and other messenger molecules amplifying the signaling of the inflammatory status.

The cytokines in concert with other secreted messenger proteins increase inflammation in the adipose tissue. Amplified inflammatory signals will attract other immune cells such as monocytes from the blood stream. The monocytes can differentiate into macrophages and the newcomer macrophages start secreting cytokines as well. You get the point. The adipose tissue is now in a vicious inflammatory cycle.

There is another aggravating factor. In lean individuals the adipose tissue secretes smaller amounts of leptin and larger amounts of adiponectin. One function of adiponectin is to suppress macrophage activity in the adipose tissue and keep the innate immune system in balance. Declining adiponectin concentrations in the adipose tissue remove the break from the immune response.

Expanding adipose tissue has the potential of becoming inflamed but the inflammation does not remain contained in the adipose tissue. Cytokines signal not only to cells in the same tissue to coordinate the immune response, but cytokines are also secreted into the blood stream and signal the inflammatory status of the adipose tissue to other tissues and organs. This chronically elevated secretion of cytokines is what we call systemic chronic inflammation or SCI for short.

The inflammation messengers cytokines coordinate the metabolism of many tissues and organs: Inflammation is not just a reaction of the immune system. Signaling molecules such as cytokines alter the entire metabolism profoundly for the short time the body is fighting the infection. Inflammation, as you all know from your last bout with flu or even soreness after an intense exercise session, triggers sickness behavior. Depending how severe the inflammation is, this will include sadness, anhedonia, fatigue, reduced libido, reduced food intake, altered sleep and social withdrawal. At a metabolic level inflammation increases insulin resistance and causes dyslipidemia. When you look at these metabolic and behavioral effects of inflammation it becomes clear that the purpose of those adjustments is to save energy and direct resources to the immune system. These reactions from other tissues ensure survival if life is threatened by a physical injury or a microbial threat. In SCI the metabolic adjustments become permanent and have a negative impact on health. LGCI or SCI? The research area of chronic inflammation has only developed over the last decades. While we understand the big picture, specific mechanisms are discussed between scientists working in the field. What makes it confusing is that there is not one commonly used term for this type of inflammation. Some researchers call it low-grade chronic inflammation (LGCI) others systemic chronic inflammation or SCI. Keep in mind that both terms signify the same process.

The circulating cytokines dock to receptors on the cell surface of other tissues. This changes the cell metabolism of those tissues as well. For example cytokines can dock to blood vessel epithelial cells triggering an inflammatory response or can dock to cells altering insulin sensitivity. Systemic chronic inflammation contributes along with other risk factors to T2D, CVD, kidney disease and other chronic diseases. Recently evidence emerged that systemic inflammation might contribute to cognitive decline during aging and dementia as well.

Not every obese person develops chronic diseases, but evidence is strong that systemic chronic inflammation triggered by an inflamed adipose tissue in obesity is the reason why non-communicable chronic diseases are much more common in obese individuals than in individuals in the normal and overweight range.

Not All Obese and Overweight Individuals Are Metabolically Unhealthy

Why are many obese individuals, but also some overweight or lean individuals, metabolically unhealthy? Why do some teenagers with obesity develop T2D and CVD? Why do others not develop those diseases until old age or not at all despite being obese all their life?

The key to definining who is metabolically healthy or not is a condition called metabolic syndrome.

Metabolic syndrome is a set of risk factors that predicts the risk for chronic diseases later in life. Five risk factors are considered:

1. Large waist circumference: People with abdominal, especially visceral obesity have a high risk for developing chronic diseases.
2. Hypertension: High blood pressure damages arteries. Constant damage to the endothelium promotes atherosclerosis which increases the risk for heart attack and stroke.
3. High blood triglycerides: Hypertriglyceridemia is often a sign of health conditions increasing the risk for atherosclerosis. Excess triglycerides contribute to the the hardening and thickening of blood vessel walls.
4. Low HDL: HDL is functioning like a little garbage truck circulating the blood vessels and picking up surplus cholesterol or cholesterol from dead cells. HDL then transports the choletsrol back to the liver for recycling. High HDL helps keep blood vessels healthy, lowering the risk for heart attack and stroke.
5. Fasting blood glucose over 100 mg/dl indicating prediabetes: High blood glucose also damages blood vessels contributing to atherosclerosis and organ damage.

If a person is diagnosed with 3 or more of those criteria, the person is diagnosed with metabolic syndrome. A diagnosis means that the person is a higher risk for type-2 diabetes, heart disease and stroke.

The main factor determining if a person with obesity is metabolicall health or not is the genetic predisposition. Genetics determines how the adipose tissue grows and how adipocyte function.

Some people have a genotype that increases adipose tissue by generating more and smaller adipocytes. This is called hyperplasia and is less connected to systemic chronic inflammation. Other people’s metabolism fills up existing adipocytes to capacity producing very large adipocytes. This is called hypertrophy. Overly large adipocytes are connected to systemic chronic inflammation.

The location of the adipose tissue is important as well. Visceral obesity—excessive adipose tissue located within the body cavity—fuels systemic chronic inflammation more than subcutaneous adipose tissue.  Even some lean individuals have excessive amounts of visceral fat and therefore develop SCI.

As people reach middle age adipose tissue location start to change. Hormonal changes in middle age promote central and visceral obesity. Details are discussed in the aging chapter.

In summary the current evidence points toward overly large adipocytes and visceral obesity as the main predictors for SCI. But, does this mean that people with this type of obesity automatically develop CVD or T2D early in life and die early?

Lifestyle plays a major role as well. Eating a diet rich in fruits and vegetables and having an active life style promote anti-inflammatory mechanisms and curb SCI. As a consequence metabolic disease progresses more slowly even if a genetic predisposition exists. Structured exercise for health seems to stimulat inflammatory processes which in turn damps down SCI.

This explains partially why some overweight and obese people stay metabolically healthy for a long time while others develop T2D already in their teens. Keep in mind that the transition between those metabolic types is fluent.

Metabolically Healthy:

• In lean people—without visceral adipose tissue accumulation—the adipose tissue functions as it should signaling satiety, helping to regulate glucose and lipid metabolism, and curbing excessive inflammation.
• An estimated 10 – 30% of obese people are metabolically healthy. Just like normal weight individuals this group of obese people doesn’t show any overt signs of metabolic disease. They tend to have very moderate SCI and only a mild metabolic dysfunction. The major question science tries to answer is if those healthy obese people also develop an unhealthy metabolic patterns with age. 

  How many people have obesity and are still metabolically healthy? Depends how metabolically healthy obesity (MHO) is defined:  In many studies metabolically healthy obesity is diagnosed if the study participants have two or less metabolic syndrome criteria. This is the reason why you read sometimes that 50% of people with obesity are metabolically healthy. But, are they healthy? A new study summarizing the existing studies questioned this definition. When they looked at the 50 % metabolically healthy people with obesity the majority of this group were not completely healthy but had only fewer and milder metabolic abnormalities. For example, using the commonly used definition people can have insulin resistance (no metabolic syndrome criterium) and still be classified as MHO. Insulin resistance is one of the strong predictors for declining metabolic health with age. When the scientists used a new, more restrictive definition only a small subset of people with obesity, around 7 %, was fully metabolically healthy. If you are interested in the entire study: Smith GI, Mittendorfer B, Klein S. Metabolically healthy obesity: facts and fantasies. J Clin Invest. 2019;129(10):3978-3989. doi:10.1172/JCI129186

   

Metabolically unhealthy:

• People with a high degree of adiposity or a genetic profile that promotes visceral adiposity tend to have systemic chronic inflammation and manifested metabolic dysfunction. The normal regulation of metabolic function is pretty much hijacked by the hormones and proinflammatory cytokines secreted by the adipose tissue. Development of chronic diseases is apparent.
• Lean people with a high degree of visceral fat due to a genetic predisposition will have increased SCI and a matabolism that is not efficietly regulated. They have an increased risk for chronic diseases.

The question is then who will transition from metabolically healthy to unhealthy obesity. As people age and have an unhealthy lifestyle chances are that their metabolic health will slowly decline. If people have a high BMI and are developing multiple risk factors, the risk for being diagnosed with a chronic disease increases. The main predictors though are insulin resistance along with increasing blood glucose over time.

In conclusion, growing adipose tissue comes with profound metabolic changes. Hunger and satiety regulation becomes progressively inefficient, hormonal changes affect the metabolism, and systemic chronic inflammation alters the immune response and affects other tissues. Our understanding of these complex processes is still limited to broad ideas. Today, research works on understanding the mechanisms that connect growing adipose tissue to chronic diseases and most importantly the reversal of those metabolic changes. An interesting field of research studies the browning of adipose tissue (white to beige adipocytes). This line of research shows that people with a higher amount of beige adipocytes tend to be not only leaner, but beige adipocytes also are asoociated with better metabolic health. 

Interested? Want to Know More?

Obesity is a major source of systemic chronic inflammation but other factors contribute as well. Here is a Nature article reviewing what we know about the intersection of systemic chronic inflammation and the development of chronic diseases:

Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822-1832. doi:10.1038/s41591-019-0675-0

If you are as fascinated by exosomes as I am, here is a great review article going into more detail:

Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977. doi:10.1126/science.aau6977