Buenos Aires 01 de Marzo del 2022
Reassessing Human Adipose Tissue
Reassessing Human Adipose Tissue
Aaron M. Cypess, M.D., Ph.D.
N Engl J Med 2022; 386:768-779 – Review Article
Adipose tissue is an underappreciated and misunderstood organ. Capable of more than doubling in mass and then returning to baseline,1 white adipose tissue (WAT) continues to play an essential role in the development of humans. WAT efficiently stores sufficient energy to free us from constantly seeking food, permitting us to devote our physical and mental efforts toward building civilization. Brown adipose tissue (BAT) consumes glucose and triglycerides, generating heat. An organ designed for nonshivering thermogenesis, BAT has enabled mammals to thrive in the current Cenozoic era. Once thought to be physiologically irrelevant in adult humans, long-term activation of BAT has been hypothesized to contribute to wide-ranging health benefits in tissues as diverse as the gastrointestinal, cardiovascular, and musculoskeletal systems.2
Highlighting the developments from the past 5 to 10 years, this review discusses the two principal facets of human adipose tissue: its functional roles related to triglyceride storage, as well as its excess in obesity, and its far-reaching, complementary physiological roles in the endocrine system.
Structure and Distribution of Adipose-Tissue Depots
Too many people are confident that they know what fat is: an undesired body appendage that they strive to reduce over their entire lives. For those who struggle to lose weight, fat is often a source of misery, not marvel. Among medical professionals, it had been disregarded to the extent that fat has merited little attention in curricula and does not even feature in atlases of anatomy.
Fortunately, the past three decades have witnessed a revolution in our understanding of and perspective on this tissue.3 Fat is not one entity; it is a collection of related but different anatomical and functional adipose-tissue depots.4,5
Derived principally from the mesoderm,6 human WAT begins to develop in the second trimester of pregnancy, and by birth, both visceral and subcutaneous depots are well established. BAT first arises during the late second trimester and protects newborns from cold as they develop the ability to shiver. In lean adults, the entire WAT depot ranges from 20 to 30 kg in women (30 to 40% of total body mass) and 10 to 20 kg in men (15 to 25% of total body mass).7
Fat mass can be estimated rapidly and in many persons with the use of inexpensive methods such as skinfold calipers, waist circumference, or body-mass index (BMI). Assessments are more accurate with bioimpedance analysis and dual-energy x-ray absorptiometry, and very precise calculations may be accomplished by means of computed tomography (CT) and magnetic resonance imaging (MRI).8 The relative amounts and distribution of adult human BAT are predictably influenced by allometric scaling. Adult mice, a common model for studies of vertebrate physiology, weigh 20 to 50 g, and BAT is 2 to 5% of their body mass. Humans are three orders of magnitude larger, so our lower ratio of surface area to volume and greater insulation from muscle and WAT reduce the need for BAT thermogenesis. The distribution of adult human BAT is also much more restricted, found only in certain anatomical depots in the neck, shoulders, posterior thorax, and abdomen.9 A unifying feature is that these depots drain directly into the systemic circulation and may lead to more rapid distribution of warmed blood to the rest of the body.
Quantification of active BAT is challenging and relies on whole-body, noninvasive imaging with the use of either positron-emission tomography–CT or MRI.10 The maximum detectable BAT mass in humans appears to be approximately 1 kg, and in adults 20 to 50 years of age, it ranges from 50 to 500 g, or 0.1 to 0.5% of total body mass, and 0.2 to 3.0% of total adipose tissue mass.9 The amount of BAT also varies according to sex, and it has an inverse association with age and BMI.11 As discussed below, how much further BAT mass can be increased in humans and whether a larger proportion could affect energy balance or metabolic health remain to be determined.
Fat tissue plays a central role in energy distribution. All food eaten by mammals consists of just three macronutrients: carbohydrates, proteins, and fats. Even though individual meals can have widely varying proportions of these three fuels, the human body is capable of metabolic flexibility, which is the ability of mitochondria to alter their substrate preference for fat as compared with carbohydrate oxidation.12 Recent research has shown that dysfunctional mitochondria lead to insulin resistance in skeletal muscle, not because of impaired flexibility in response to substrate availability but because of an overall decrease in substrate oxidation.12 Therefore, overfeeding of any one of the macronutrients — carbohydrates, proteins, or fats — ultimately leads to a positive energy balance and weight gain.13 The contribution of macronutrient composition to energy expenditure and the development of obesity and metabolic disease is an area of active debate.14 The primary function of WAT is to store energy in the form of triglycerides, yet there are substantial, clinically relevant physiological differences among the various WAT depots.15 Metabolic health risks are therefore due at least as much to the location of excess triglyceride storage as to the overall fat mass of the body.16 WAT is commonly separated into visceral fat and subcutaneous fat, which confer negative and neutral or positive metabolic effects, respectively.17 Visceral fat can be divided into multiple distinct regions with different metabolic risks.
On the basis of microscopic anatomy and cell physiology, it is more appropriate to refer to fat as adipose tissue because it is composed of multiple distinct cell types. There are the adipocytes themselves but also the stromal vascular fraction — fibroblasts, blood and blood vessels, macrophages and other immune cells, and nerve tissue. Relatively recent forms of technology involving single-cell and single-nucleus RNA sequencing, which are becoming an integral part of mapping tissues and their complexity, have identified numerous cell subtypes that play critical roles in regulating adipogenesis, thermogenesis, and interorgan communication.25 In addition, the various proteins and proteoglycans in the extracellular matrix play an active role in the function of both WAT and BAT.16,26
Many features of adipose-tissue depots, such as location, size, and metabolic behavior, are influenced by genetic background and sex.27 Beyond that, adipose tissue is a dynamic organ. The widely held belief that humans are born with all the fat cells they will ever have, which are capable only of enlarging or shrinking, is now understood to be incorrect. Innovative use of isotopic labeling has enabled researchers to measure new adipogenesis. These studies showed that adipogenesis continues throughout life, with a median turnover rate of 8% per year, indicating an entire replacement of the adipocytes in the body every 15 years.28 For perspective, this rate is similar to that of osteocytes and faster than the turnover of many cardiomyocytes.29 Adipocyte precursor cells, known as preadipocytes, are present in the stromal vascular fraction and perivascular tissue, which are capable of self-renewal.30 Growth of the adipocytes comes both from hypertrophy, the enlargement of cell size, and hyperplasia, the increase in cell number.31 The balance among hypertrophy, hyperplasia, fibrosis, and lipolysis in both visceral and subcutaneous WAT is associated with different risks for progression to physiological dysfunction.32 The newfound diversity and capability have led to the recognition that mammalian adipose tissue is a “polychromatic” organ. In addition to white and brown, there are distinct thermogenic adipocytes, termed “beige/brite,” which have features of both white and brown adipocytes, and pink adipocytes in breast tissue,33,34 as well as fat in the bone marrow and dermis, each with a distinct physiological role.35,36
Function and Communication
WAT has three commonly understood and related macroscopic functions. It stores food calories, creates a layer of thermal insulation, and provides mechanical protection, which is important for resisting infection and injury.37 Insulin is the principal driver of fuel absorption and storage, with adipose tissue responsible for 5% of insulin-mediated glucose uptake in adults who are lean and 20% in those who are obese.38 Until three decades ago, these physiological roles were all that most people considered when thinking about WAT, but the discoveries of white adipocyte–derived hormones such as leptin and adiponectin made clear that WAT is also an endocrine organ39-43 . Beyond these hormones, adipocytes and the other resident cell types produce dozens of other adipokines that affect local and distant physiology, such as proinflammatory tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1, and the sex hormone estrogen.44 WAT as a mesodermal organ communicates its functional status at the autocrine, paracrine, and endocrine levels. For example, pregnancy requires a sufficient long-term supply of energy, and WAT is essential for the proper function of the reproductive system, which includes the secretion of regulatory and sex hormones and lactation. Too little WAT, as seen in anorexia nervosa and lipodystrophies, interrupts menstruation.45 Too much WAT leads to early puberty.46 WAT also uses interorgan signaling to coordinate the storage and consumption of nutrients with the liver and skeletal muscle.47
The discovery of leptin three decades ago48 heralded a new era in obesity medicine but not as originally anticipated. Leptin does not induce satiety, but low leptin levels signal low energy stores and starvation. People with obesity have leptin resistance such that exogenous administration does not lead to appetite suppression or weight loss, except in persons with congenital leptin deficiency, which is extremely rare. Various studies of the effects of leptin have led to new insights regarding the control of food intake by the hypothalamus and other brain regions.
Adiponectin regulates glucose and lipid metabolism and promotes a metabolic profile that is antiatherogenic, antiinflammatory, and insulin-sensitizing.49 Advances in understanding adipose tissue as an endocrine organ have been supported by the identification of non–peptide-signaling species that have local and systemic effects. Bioactive lipids such as 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) and 12-hydroxyeicosapentaenoic acid (12-HEPE) are released by BAT and stimulate glucose and fatty acid uptake in BAT and muscle, thereby supporting ongoing thermogenesis.50 BAT also releases exosomal microRNAs that can regulate gene expression in other tissues such as the liver.51
WAT and, more recently, BAT have been identified as integral and regulatable components of lipoprotein and bile acid metabolism. Triglyceride-rich lipoproteins, in the form of chylomicrons from a meal, and liver-derived very-low-density lipoprotein deliver their lipid payloads to WAT and BAT. Studies in rodents have shown that prolonged BAT activation leads to changes in liver cholesterol homeostasis, bile acid metabolism, and the composition of the microbiome.52 More than a decade after the discovery of BAT as a functional tissue in adult humans,53 there is nascent evidence suggesting that BAT activation may also lower the risk of atherosclerosis and drive the consumption of glucose and lipids by skeletal muscle.54
Both WAT and BAT participate in immunomodulation, the suppression and activation of the immune system, and each tissue releases its distinct profile of mediators of the complement system.41 Obesity leads to WAT-derived proinflammatory cytokines such as TNF-α, interleukin-1β, interleukin-6, and interferon-γ. These compounds activate and recruit macrophages, which can increase from less than 10% to nearly 40% of the total number of cells in adipose tissue.55 Dendritic cells and B cells join to induce the expansion of CD4 and CD8 T cells. One important consequence of the resulting adipocyte insulin resistance and macrophage activation is increased fatty acid release, which ultimately drives hepatic gluconeogenesis and hyperglycemia.56 In contrast, BAT is particularly resistant to obesity-induced inflammation,57 and in rodent models, BAT has been found to express high levels of programmed death ligand 1, which reduce T-cell activation58 and may improve insulin sensitivity.
Obesity and a Complication of too much WAT
The overweight and obesity pandemics affect more than 70% of the U.S. population59 and are projected to increase in prevalence over the next 30 years.60 In parallel, there has been a rise in obesity-related conditions such as type 2 diabetes, precocious puberty, cardiovascular disease, and several cancers.61 Even more troubling is the observation that the rates of obesity are increasing much faster among children than among adults and that obese children are more likely to become obese adults at high risk for severe health complications.62 Adequate responses to the clinical and societal sequelae of these trends require a more accurate understanding of the specific effects of the different WAT and BAT depots. Current assessments across adult and pediatric populations often use BMI exclusively, which, at minimum, requires adjustments for age, sex, and genetic and ethnic backgrounds.63 BMI cannot provide information about WAT distribution or the predispositions of specific depots for their distinctive pathophysiology or the likelihood of a response to targeted therapies. Going forward, it will be particularly important to conduct large studies of epidemiologic trends that go beyond BMI and incorporate other estimates of the distribution of WAT depots, including waist circumference64 in order to better understand the role of WAT distribution in obesity-related metabolic disease.
Although it is correct to attribute the increasing rates of obesity to excessive triglyceride storage in WAT, that picture is too simplistic and impedes the development of treatment strategies. Since the start of the obesity pandemic in the 1970s, the principal contributing causes and their individual influence remain unknown. The roles of portion sizes, specific food classes, particular ingredients, and changes in patterns of activity are being investigated.65 Concomitantly, it is useful to conceptualize obesity as a disease of the brain that is manifested as an excess of WAT and dysfunctional BAT. Studies have shown the pernicious cycles that accelerate the development of obesity once a person has begun to gain weight.66 The hypothalamic region of the brain is of increasing interest because it integrates multiple physiological signals from the body, transmits them to different brain regions, and coordinates the regulation of diverse processes, including body temperature and feeding. Studies in rodents have mapped the neuronal pathways that interpret signals from feeding and from the WAT itself regarding its mass and then integrate those signals into homeostatic and hedonic messages, which interpret the availability of energy stores and the emotional meaning of specific foods, respectively.67 Besides the WAT, obesity also disrupts the ability of the hypothalamus to stimulate BAT energy expenditure.67 Obesity cannot be viewed simply as a failure of willpower. Instead, it is a complex interplay among hundreds of genes, socioeconomic demands, and personal decision making that ultimately leads to a long-term increase in average caloric intake over energy expenditure.68
Connections among obesity, its metabolic complications, and genetic influences have become more established through genomewide association studies. These large-scale global population studies have identified new genetic loci in the central nervous system, indicating a potentially genetic component of aspects of lifestyle, as well as insulin resistance, linking central obesity to metabolic dysregulation and, ultimately, the risk of cardiovascular disease.69 However, it is critical to appreciate the distinction between the heritability of obesity and the effect of any one gene. Genetic influences on obesity are substantial, up to 70% on the basis of studies involving populations of predominantly European origin,70,71 but this strong effect should not be misinterpreted to mean that there is a single “fat gene.” Currently, only 20% of the entire phenotypic variation in obesity can be explained by the thousands of loci identified so far.72 Adding further complexity is the effect of epigenetics — heritable yet reversible changes in gene function that do not involve the DNA code itself. Obesity and even dietary components can have profound phenotypic effects.73 Efforts are now being focused on how the mechanisms by which the genes and the associated physiological pathways affect short- and long-term energy imbalances and the subsequent health complications.
How does excess adipose tissue lead to disease? Like no other cells, white adipocytes are adept at enlarging and can swell from a diameter of 30 to 40 μm to more than 100 μm, an increase in volume by a factor of more than 10. Starting in early adulthood, lean U.S. adults spend the next decades challenging their adipocytes by gaining on average 0.5 kg (1.1 lb) per year, with even higher weight increases among the overweight and obese,74 putting an enormous demand on the WAT depots to store triglycerides by the fifth and sixth decades of life.75
Anatomical location and genetics largely determine the proportional increase in adipocyte size and number and the physiological responses. For example, people whose subcutaneous depots maintain smaller adipocytes have fewer metabolic complications.31 Furthermore, in people who are genetically predisposed to impaired catecholamine-mediated lipolysis, white adipocytes become very large,32 a situation exacerbated by a genetic inability to recruit new adipocytes.76 As obesity progresses, preadipocyte differentiation becomes dysfunctional, leading to reduced insulin signaling, glucose uptake, and adiponectin release by the mature adipocytes.77,78 Ultimately, hypertrophic WAT growth and expansion restrict the ability of oxygen to diffuse from the capillaries into the adipocytes.77 This hypoxia constitutes a biologic red alert for the cells, altering the expression of more than 1000 genes and triggering a series of interconnected responses that ultimately lead to local resistance to both insulin and adrenergic signaling, increased inflammation, and cellular damage. Failure of the adipose tissue to continue expanding leads to overflow and subsequent deposition of triglycerides throughout the body, with ectopic accumulation in the liver and skeletal muscle. The extent of this lipotoxicity is an important determinant of the development of metabolic dysregulation, type 2 diabetes, and cardiovascular disease.79
This milieu leads to immune-system dysfunction and is thought to contribute to increased morbidity and mortality from infectious disease, currently highlighted by the worrisome epidemiologic reports about people with obesity and coronavirus disease 2019.80 Obesity is also associated with an increased risk of many types of cancer, including cancer of the breast, uterus, ovary, esophagus, stomach, colon or rectum, liver, gallbladder, pancreas, kidney, thyroid, and meninges, as well as multiple myeloma,81 but the precise mechanisms are currently unclear.
Three causative agents identified so far are hyperinsulinemia, factors released during chronic inflammation, and increased estrogen production.
Given the scope of disorders, the question that arises is whether excess stored triglycerides are ever benign. A metabolically healthy obese phenotype has been postulated, which has been associated with several aspects of adipocyte function, such as the release of specific adipokines.82 Whether obese persons who are metabolically healthy are nevertheless on an inexorable path toward metabolic disease remains to be determined.83
The riskiest approach to human adipose tissue is to dismiss its importance. WAT lies at the heart of the obesity pandemic, and its response to excess calories has an effect on every organ system, with profound effects on morbidity and mortality worldwide. The past decade, and particularly the past 5 years, has seen an explosive growth in our understanding of adipose tissue, with work that recognizes human WAT and BAT as organs that have anatomical, functional, and genetic diversity. Going forward, fat will ideally be appreciated for what it is, a polychromatic tissue, which is as relevant and influential as other organs for sustaining human health.
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PD: Figures and References (100) in original article