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Leptin, which is a peptide hormone expressed by adi- pocytes that is essential for body weight control and many other functions, was discovered in 1994. Its dis- covery established adipose tissue as an essential endo- crine organ 1. Since then, research has revealed many adipose tissue-derived peptide hormones (adipokines) and non-peptide endocrine factors, which are the topic of this Review (Box 1; Fig. 1). Important highlighted aspects include regulation of the expression and secre- tion of adipose tissue endocrine factors as well as their modes of action. We focus on the impact of the acti- vation state of adipose tissue depots for the secretion of endocrine factors. Moreover, we discuss the role of brown adipose tissue (BAT) compared with that of the various white adipose tissue (WAT) depots. In addition, we present the current views of how adipose tissue hor- mones contribute to the development and progression of cardiometabolic diseases in animal models and humans, including therapeutic implications. Notably, only a few of the factors released by adi- pose tissue are established endocrine hormones, and many of them, especially those molecules secreted by non-adipocytes, exert predominantly paracrine func- tions^2. Only leptin and adiponectin are currently gene- rally accepted as true adipose tissue-derived endocrine
hormones, which are released from adipose tissues and exert defined responses in target organs. Nevertheless, many studies indicate endocrine roles for various other factors. Overall, unbiased approaches have found a very large number of molecules with proven or potential sig- nalling activity that are secreted by adipocytes, which are lipid-storing connective tissue cells found throughout the body, and other adipose tissue cells^3. For example, a 2018 proteomic study compared the secretome of mouse white and brown adipocytes and identified more than 1000 unique secreted proteins, of which more than 100 were differentially released between white and brown adipocytes 4. Another comprehensive bioinformatics study, based on RNA sequencing data from more than 100 different mouse strains, addressed endocrine inter- actions between adipose tissue and various organs. Using this elegant approach, researchers identified sev- eral novel adipose tissue-derived endocrine candidates, such as lipocalin 5 (reF.^5 ). Owing to the sheer number of potential adipose tissue-derived endocrine factors, we can cover only a small number in this Review. We focus on hormones where endocrine functions have been most compre- hensively studied and on recently identified candidates. Furthermore, factors were selected in a way to represent
The endocrine function of adipose
tissues in health and cardiometabolic
disease
Ludger Scheja and Joerg Heeren *
Abstract | In addition to their role in glucose and lipid metabolism, adipocytes respond differentially to physiological cues or metabolic stress by releasing endocrine factors that regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines), lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets; for example, adiponectin and leptin signal through their respective receptors that are expressed in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to be identified. Furthermore, many of these hormones are also produced by other organs and tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this Review, we discuss the functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and we highlight how these factors contribute to the development of cardiometabolic diseases. We also cover how this knowledge can be translated into human therapies. In addition, we discuss recent findings that emphasize the endocrine role of white versus thermogenic adipocytes in conditions of health and disease.
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. *e-mail: [email protected] https://doi.org/10.1038/ s41574-019-0230-
Nature reviews |^ Endocrinology
the diverse primary biological functions of these mole- cules beyond classical peptide hormone signalling. For each molecule, we critically discuss the level of experi- mental evidence, important differences between rodents and humans (if they occur) and the gaps in knowledge identifying the molecule as a true endocrine factor.
The diversity of adipose tissue depots White adipose tissue WAT is the main site of energy storage in the body and is present in multiple anatomical locations6,7. White adipo- cytes are the predominate cell type found in WAT, and contain low amounts of mitochondria and none of these mitochondria contain uncoupling protein 1 (UCP1). In the postprandial state (that is, after a meal), white adipo- cytes take up fatty acids carried by circulating lipopro- teins, convert them into triglycerides and store these in a large intracellular lipid droplet. By contrast, between meals and in other catabolic states, WAT releases free fatty acids (FFAs) liberated by intracellular lipolysis into the bloodstream to provide other organs with energy 8. In adipocytes, catecholamines, which originate primar- ily from the sympathetic nervous system, are the major lipolytic signalling molecules and increase intracellular cyclic AMP levels by stimulating β-adrenergic receptors. Moreover, other hormones, such as natriuretic peptides^9 , induce catabolic signalling by elevating intracellular cyclic AMP or cyclic GMP concentrations. By contrast, in the postprandial state, insulin inhibits lipolysis and causes the uptake of fatty acids and glucose into WAT. Not surprisingly, several endocrine factors released from adipose tissues are regulated by insulin or sympathetic tone, as described in detail later. During periods of calorie surplus, WAT mass expands by increasing both the size (hypertrophy) and the number of adipocytes (hyperplasia). However, chronic activation of this process becomes detrimental, leading to obesity. In obesity, excessive WAT expansion is accompanied by structural and cellular changes in the tissue, including
adipocyte hypertrophy and fibrosis^10 , local inflammation, infiltration of immune cells, polarization of macrophages from an anti-inflammatory to a pro-inflammatory pheno- type (Fig. 2), altered lipid handling in macrophages, decreased response of adipocytes to insulin (insulin resistance) and a disturbed metabolism11–14. Adipocyte insulin resistance leads to insufficient lipid retention in WAT and, consequently, ectopic lipid accu- mulation occurs in organs such as the liver and skeletal muscle. This accumulation is hypothesized to disturb insulin signalling in those organs and further promote the development of systemic insulin resistance and type 2 diabetes mellitus (T2DM) 15 (Box 2). Importantly, fatty acids released from white adipocytes, especially saturated fatty acids such as palmitic acid, alter the production and secretion of inflammatory cytokines and adi- pokines from hypertrophic WAT, thereby contributing to obesity-related organ dysfunction (see later)8,10,11. Of note, not all WAT depots are associated with equal disease risk in human obesity. The amount of visceral abdominal WAT, as compared with subcutaneous WAT, is tightly linked with insulin resistance and metabolic disease in humans7,16,17. The reason for this association is not fully clear but might be partially due to the drainage of visceral fat into the portal vein^7. This anatomical situ- ation means that molecules released from visceral WAT can reach the liver in higher concentrations than mole- cules derived from subcutaneous WAT 7. Importantly, unhealthy obesity is associated with intra-abdominal expansion of insulin-resistant and inflamed WAT 16. As described later, some adipokines are enriched in visceral WAT and probably have a particular impact on the liver in the context of visceral obesity.
Brown adipose tissue BAT is a highly vascularized organ rich in brown adipo- cytes, which is unique to mammals and functions to gene- rate heat by metabolizing fatty acids and glucose in a process called ‘adaptive (non-shivering) thermogenesis’. In contrast to white adipocytes, brown adipocytes have multiple small lipid droplets as well as a much higher content of mitochondria, and, importantly, these mito- chondria contain UCP1, which shuttles protons back into the matrix and uncouples the electron transfer chain from ATP synthesis, thereby generating heat^18. The pro- cess of adaptive thermogenesis is triggered by increased sympathetic tone or by the action of endocrine hor- mones such as natriuretic peptides and secretin9,19, which stimulate intracellular lipolysis in brown adipocytes.
Key points
- White and brown adipocytes secrete many peptide hormones (adipokines), bioactive lipids (lipokines) and RNA molecules with local (paracrine) and systemic (endocrine) effects on the brain, pancreatic β-cells, the liver, skeletal muscle and the cardiovascular system.
- Production and secretion of adipokines and lipokines is dependent on the energy status of adipose tissues. Through endocrine action, these factors contribute to systemic energy metabolism by regulating appetite, thermogenesis, glucose metabolism and lipid metabolism.
- Many peptides that were initially described as adipokines are secreted by endothelial and immune cells located in adipose tissues, as well as by other organs, which means the endocrine contribution of adipocytes can be difficult to ascertain.
- In healthy states, white and brown adipose tissues secrete endocrine factors that maintain organ functions and metabolic homeostasis.
- In obesity, hypertrophic adipocytes and adipose tissue-resident immune cells accelerate a chronic, proinflammatory profile with altered secretion of adipokines and lipokines, thereby exacerbating cardiometabolic disease.
- Preclinical and clinical studies show that activating or inhibiting the signalling of specific adipokines or lipokines could be an approach suitable to treat or prevent the development of cardiometabolic diseases. However, in almost all cases, efficacy and safety in humans needs to be proven.
Box 1 |^ Adipokines and lipokines In addition to their prominent role in fatty acid and energy metabolism, adipocytes and other cells in adipose tissue secrete a large number of different regulatory peptides (adipokines)^8 ,^30 ,^31 , as well as regulatory lipid species (lipokines)^8 ,^90 ,^97 ,^104. These factors can act on neighbouring cells (paracrine action) or on cells in other organs (endocrine action) to specifically regulate or modulate diverse processes, including lipid and glucose homeostasis, energy balance, inflammation and tissue repair.
Uncoupling protein 1 (UCP1). A unique proton transporter that shuttles protons back into the mitochondrial matrix and uncouples the electron transfer chain from ATP synthesis, a process that generates heat.
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BAT, these small amounts of tissue still have an impact on whole body metabolism^21. BAT also produces a num- ber of endocrine factors (Figs. 1,2). Although the much larger WAT depots are probably the dominant source of most circulating adipose tissue factors, especially in humans, some hormones are selectively induced in BAT under certain conditions and probably act in an endocrine fashion, as described later.
Organ-associated adipose tissue depots Some specialized adipose tissue depots are closely asso- ciated with other organs and may affect these organs by contributing to the tissue microenvironment. One example is bone marrow adipose tissue (BMAT), which is particularly abundant in the medulla of long bones. The data available suggest that bone marrow adipocytes have primarily local functions such as the regulation of bone turnover^23 and haematopoiesis^24. In addition, bone mar- row adipocytes might also have systemic effects through secretion of the adipokine adiponectin^25 (see later).
Arteries and arterioles are surrounded by adipocytes that share features of brown and beige adipocytes, which comprise the perivascular adipose tissue (PVAT). These cells are involved in the regulation of vasodilation, pro- vide mechanical support to the vessel, buffer excessive fatty acids and release paracrine hormones 26. Of note, increased inflammation in PVAT is associated with higher cardiovascular disease risk in humans and increases the development of atherosclerosis in mice26–28. Analogous to PVAT, a layer of adipose tissue covers the myocardium and the coronary arteries of the heart. This epicardial adipose tissue (ECAT) is functionally similar to PVAT and shares the microcirculation with cardiomyocytes. Consequently, ECAT can have a negative impact on the myocardium in states of metabolic inflammation^29. In conclusion, local adipocytes are closely connected with the cells constitut- ing the cardiovascular system, conferring both protection from disease and increased risk of disease. Of note, most studies investigating adipose tissue biology focus on classical WAT and BAT depots. As such,
- Inactivity
- Thermoneutrality
- Caloric excess
- Exercise
- Cold exposure
- Caloric restriction
Hypertrophic WAT and whitened BAT Healthy WAT and active BAT Saturated FFAs Anorexigenic peptide Anti-inflammatory lipids Anti-inflammatory peptides Proinflammatory peptides Prothermogenic molecules
Proinflammatory tissue-resident immune cell Anti-inflammatory tissue-resident immune cell
↑ ↑ Leptin
↓ ↓ Leptin ↓ Palmitoleate, FAHFAs? ↓ Adiponectin, omentin, NRG4 ↑ Adiponectin, NRG
↓ CXCL14 ↑ CXCL14, 12,13-diHOME
↑ RBP4, FABP4, resistin, IL-6 ↑ IL-
WAT BAT
Fig. 2 |^ Endocrine factors released by healthy and unhealthy adipose tissues. In response to chronic energy excess, an infiltration of proinflammatory immune cells can be observed in adipose tissue, which develops a hypertrophic white adipose tissue (WAT) and whitened brown adipose tissue (BAT) phenotype, a hallmark of unhealthy obesity. In contrast, energy expenditure or decreased food intake results in healthy WAT and BAT, which is characterized by the presence of anti-inflammatory immune cells and by active thermogenic brown and beige adipocytes. Both healthy and metabolic disease states are accompanied by altered secretion of adipose tissue hormones as indicated by the arrows. Overall, the changes in hypertrophic WAT contribute to insulin resistance, impaired glucose and lipid metabolism and low-grade systemic inflammation. In catabolic states, thermogenic adipocytes secrete various endocrine factors that ensure metabolic homeostasis and tissue remodelling. CXCL14, C-X-C motif chemokine ligand 14; 12,13-diHOME, 12,13-dihydroxy- (9 Z )-octadecenoic acid; FABP4, fatty acid-binding protein 4; FAHFAs, fatty acid esters of hydroxy fatty acids; FFAs, free fatty acids; NRG4, neuregulin 4; RBP4, retinol-binding protein 4.
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the relevance of PVAT, ECAT and BMAT for endocrine hormonal regulation requires further investigation. A general drawback of studying specific WAT depots is the lack of genetic intervention tools, for example, mouse lines deficient for a gene of interest in specific adipose tissue depots. Currently, depot-specific in vivo research is based on cumbersome surgical procedures such as excision and transplantation. For those WAT depots, a more extensive use of local genetic manipulation (for example, using adeno-associated virus vectors) might be useful to decipher the functional role of WAT as source of paracrine or endocrine factors.
Adipocyte-enriched endocrine factors Numerous regulatory factors secreted from adipose tis- sue with impact on adjacent or remote tissues have been identified^30 (Fig. 1; TABLes 1,2) and discovery is ongoing^5. Notably, of these factors only leptin and adiponectin are selectively expressed in adipocytes and also well established as endocrine hormones that act on specific receptors in remote target organs. In this section we describe these two classical adipokines, as well as other adipokines, lipid hormones and regulatory RNAs that are predominantly produced by adipocytes or adipose tissues and that exert a defined endocrine function. For each factor, we discuss the level of evidence indicating that it is part of a bona fide endocrine axis.
Leptin and adiponectin Leptin. The obesity gene (ob) encodes an adipokine, called leptin, which is almost exclusively expressed in adipocytes 1 (TABLe 1). Leptin-deficient ob/ob mice have an extremely obese phenotype, which is currently explained by the essential role of leptin in suppressing appetite and promoting energy expenditure through receptors in the central nervous system 31 ; however, the latter finding was challenged by a 2017 study demon- strating that leptin regulates heat loss rather than energy expenditure^32. Importantly, rodents or humans that lack either leptin or the leptin receptor (LEPR) are not only very obese but are also hyperglycaemic and extremely insulin-resistant 31,33^. These metabolic derangements are not caused by excessive adipose tissue mass but are due to the lack of leptin, as hyperglycaemia and insulin resistance are also present in lipodystrophy, a condition of very low leptin levels 31. In addition to its
role in metabolism, leptin has substantial effects on the hypothalamus–pituitary hormonal axis, the regulation of fertility, the immune system and bone turnover^31. In healthy conditions in humans and rodents, cir- culating leptin levels correlate positively with adipose tissue mass and leptin levels decrease sharply during pro- longed fasting^34 , but do not substantially change between meals^35. Thus, low plasma leptin levels can be regarded as an endocrine signal reflecting depleted adipose tissue energy stores and high energy demand. In line with this notion, low plasma leptin concentration not only fosters increased energy intake but is also causally involved in starvation-associated alterations such as increased corti- costerone and decreased thyroid hormone levels, gonadal hypoactivity and suppression of the immune system^36. Leptin is expressed in all types of adipose tissues, with a preference for subcutaneous WAT in humans^37 , and is predominantly regulated at the transcriptional level 38. In the fasted state, the sympathetic nervous system act- ing on adipocyte β-adrenergic receptors is the principal leptin-lowering mechanism39–41. By this mechanism, the secretion of leptin is tightly coupled to nutritional state and thus can mediate physiological adaptations. LEPR is a type I cytokine receptor that is expressed in many cell types both in the central nervous sys- tem and in the periphery. In the brain, leptin signal- ling is important for mediating the metabolic effects of leptin, as demonstrated by elevated levels of body fat, glucose and insulin in neuron-specific but not in hepatocyte-specific LEPR-deficient mice 42. Evidence is accumulating that all the major metabolic effects of leptin are linked to leptin signalling in specific neurons or areas of the brain, resulting in increased sympathetic flow to adipose tissues and subsequent higher energy expenditure 39,43^ , decreased heat loss^32 and the suppres- sion of appetite 44,45^ , as well as the reduction of hepatic gluconeogenesis and the prevention of peripheral insulin resistance46,47. Of note, two distinct neuron classes in the arcuate nucleus of the hypothalamus have been identi- fied as key leptin-responsive neurons: the agouti-related protein neurons and the pro-opiomelanocortin neurons. Selective knockdown of LEPR in either of these neuron classes or re-expression on a receptor-deficient back- ground had substantial metabolic effects47,48. The meta- bolic phenotype induced by such selective knockdown is not as pronounced as that associated with systemic LEPR knockdown, which suggests the importance of LEPR expressed in other parts of the brain (for example, the hindbrain)^44. Notably, LEPR signalling in the periphery is also relevant. For example, leptin could be antiatherogenic, as indicated by increased neointima formation in an endothelial cell-specific Lepr-knockout mouse model^49. Leptin signalling also occurs in pancreatic β-cells 50,^. In vitro studies found that leptin signalling inhibits insulin secretion and increases the survival of β-cells 50,51. However, a 2015 study using a mouse model with LEPR knockdown restricted to β-cells found no evidence of hyperinsulinaemia or disturbed glucose homeostasis 52. Thus, leptin signalling in β-cells affects insulin secretion in vitro, but is seemingly not essential for maintaining functionality of β-cells in vivo. Overall, leptin signalling
Box 2 | Unhealthy adipose tissues In obesity, adipose tissues can become unhealthy when adipocytes expand owing to chronic energy excess. In this state, adipose tissues contain large (hypertrophic) adipocytes that are insulin-resistant, lose their ability to adequately store triglycerides and display impaired energy expenditure^8 ,^10 ,^15. Consequently, fatty acids are released into the circulation and accumulate in other organs, causing cellular stress and disturbed metabolism, which is a hallmark of chronic metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease and nonalcoholic steatohepatitis^8 ,^10 ,^11 ,^15. In addition, the altered secretion of endocrine factors from hypertrophic adipose tissues contributes to pathological changes in other organs^8 ,^30.
Lipodystrophy A genetic or acquired condition that is characterized by lack of adipose tissue, insulin resistance and hyperglycaemia.
Neointima Pathological thickening of the subendothelial layer (intima) of arteries due to atherosclerosis or other arterial injuries
Nature reviews |^ Endocrinology
Table 2 |^ regulation, signalling and function of adipose tissue hormones Endocrine factor regulation of secretion Molecular signalling (receptor)
Physiological functions
Adipocyte-enriched endocrine factors Leptin • Increased by fat mass
- Decreased by β-adrenergic signalling
- Decreased by prolonged fasting
Receptor ligand (LEPR) CNS signalling
- Increased starvation response
- Decreased appetite
- Increased energy expenditure
- Decreased heat loss
- Increased hepatic gluconeogenesis
- Decreased insulin resistance Peripheral signalling
- Decreased insulin secretion
- Decreased atherogenesis Adiponectin • Increased by β-adrenergic signalling
- Decreased by endoplasmic reticulum stress
- Decreased by oxidative stress
- Decreased by obesity
Receptor ligand (ADIPOR1, ADIPOR2)
- Decreased inflammation
- Increased insulin sensitivity
- Increased fatty acid catabolism
- Decreased gluconeogenesis
Adipsin • Decreased by insulin
- Decreased by obesity (mice)
Complement factor D, generation of complement factor C3a
- Decreased inflammation by clearance of dead cells
- Increased inflammation by chemotaxis
- Increased insulin secretion via C3a receptor FABP4 Increased by obesity Cytosolic fatty acid binding, extracellular mechanism unknown
- Increased gluconeogenesis
- Increased insulin resistance
- Increased atherogenesis NRG4 • Increased by thermogenic activation
- Decreased by obesity
Receptor ligand (ERBB3, ERBB4)
- Decreased hepatocyte DNL
- Decreased hepatocyte death
- Decreased insulin resistance
- Decreased steatohepatitis
- Increased adipose tissue angiogenesis
- Increased adipose tissue innervation Adipocyte-derived exosomal microRNAs Exosomal miR-99b Unknown Decreased translation Decreased liver FGF21 expression Exosomal miR-92a Decreased by thermogenic activation
Decreased translation • Decreased angiogenesis
- Decreased obesity Lipokines FAHFAs from DNL • Increased by glucose metabolism
- Increased by DNL
Receptor ligand (GPR120, GPR40), others?
- Increased glucose tolerance
- Increased GLP1 secretion
- Increased insulin secretion Palmitoleate Increased by WAT DNL Unknown • Decreased inflammation
- Decreased atherogenesis
- Increased glucose homeostasis 12,13-diHOME • Increased by cold exposure
- Increased by exercise
Unknown • Increased BAT activity
- Increased skeletal muscle fatty acid oxidation
- Increased fatty acid transport Adipokines also released by hepatocytes FGF21 Liver
- Increased by starvation
- Increased by carbohydrate overfeeding BAT
- Increased by thermogenic activation
- Increased by transplantation
- Increased by cellular stress
- Increased by hypertension
Receptor ligand (FGFR with β-klotho)
Liver
- Increased hepatic gluconeogenesis
- Increased fatty acid oxidation
- Increased ketogenesis
- Increased sympathetic tone
- Increased insulin sensitivity BAT
- Improved glucose homeostasis
- Decreased cardiac hypertrophy
NATURE REVIEWS |^ Endocrinology
in liver and skeletal muscle, increased glucose uptake in muscle and WAT and decreased WAT inflammation^53. Of note, adiponectin also has a protective effect on pancreatic β-cells. Local inflammation and stress induced by the deposition of lipotoxic lipids (for exam- ple, ceramides and diacylglycerols) are important mecha- nisms causing dysfunction 63 and partial β-cell loss during progression from simple insulin resistance to T2DM. Adiponectin receptors are expressed by β-cells, and evidence suggests that adiponectin, in line with its general anti-inflammatory role, prevents β-cell apoptosis and dysregulation of insulin secretion in vitro^51. Mouse experiments using a transgenic model of limited β-cell destruction found that adiponectin was essential to pre- vent hyperglycaemia and loss of pancreatic islet mass, in part by decreasing levels of lipotoxic ceramides 63. Notably, adiponectin supports the regeneration of β-cells in vivo by inducing expression of HNF4A, a master transcription factor of β-cells^63. Beyond β-cells, adiponectin exhibits strong anti-inflammatory and antifibrotic activities in many organs by acting on macrophages and fibrogenic cells 53,64,65^. Accordingly, a protective role of adiponec- tin could be identified in atherosclerosis 66 , gestational diabetes 67–69^ and nonalcoholic fatty liver disease 70,^.
Taken together, the findings show that adiponectin is an endocrine hormone that is released by adipocytes, with proven homeostatic functions, particularly in the context of chronic metabolic stress.
Other adipokines Adipsin. The first identified adipokine was adipsin, which was originally described as a secreted serine pro- tease expressed in mature adipocytes but not in undif- ferentiated precursors^72. Plasma adipsin is derived from adipose tissues (Fig. 1), which are the major site of its expression^73. Adipsin is also known as complement fac- tor D, which is a rate-limiting component of the alterna- tive complement pathway. In humans, the activity of the alternative complement pathway correlates with adverse outcomes, for example in cardiovascular disease 74 , indicating that adipsin has the potential to modulate inflammatory events in remote organs. Depending on the context, the alternative pathway might fuel inflam- mation by the production of chemotactic molecules, or might dampen inflammation by opsonization and the removal of dead cells. Studies using mouse disease models suggest that the net outcome of adipsin action depends on dis- ease severity; models with more pronounced tissue
Endocrine factor regulation of secretion Molecular signalling (receptor)
Physiological functions
Adipokines also released by hepatocytes (cont.) RBP4 Increased by obesity Vitamin A-binding protein, receptor ligand (STRA6, TLR4)
- Increased inflammation
- Increased insulin resistance
IGF1 • Increased by growth hormone
- Increased by BAT transplantation
Receptor ligand (IGF1R) BAT
- Increased glucose homeostasis in T1DM Adipokines also released by immune cells CXCL14 Increased by thermogenic activation
Receptor ligand (receptor unknown)
- Increased WAT browning
- Decreased WAT inflammation IL-6 • Increased by inflammatory cytokines
- Increased by lipolysis
- Increased by obesity
Receptor ligand (IL-6RA, glycoprotein 130)
- Increased and/or decreased inflammation
- Increased hepatic gluconeogenesis
Resistin Increased by inflammation Receptor ligand (TLR4, others?)
- Increased inflammation
- Increased insulin resistance Ubiquitously expressed adipokines with endocrine potential GDF15 • Increased by obesity
- Increased by severe illness
- Increased by IL-4 and IL-
- Increased by oxidative stress
Receptor ligand (GFRAL)
- Decreased inflammation
- Increased glucose homeostasis
- Pleiotropic effects
NAMPT/visfatin • Increased by obesity
- Increased by insulin resistance
NAD+-synthesizing enzyme, receptor ligand?
- Increased lymphocyte growth
- Increased inflammation
- Increased apoptosis Omentin Decreased by hyperinsulinemia Lectin, receptor ligand? • Decreased insulin resistance
- Decreased atherogenesis Vaspin Increased by obesity Protease inhibitor Decreased insulin resistance ADIPOR, adiponectin receptor protein; BAT, brown adipose tissue; CNS, central nervous system; CXCL14, C-X-C motif chemokine ligand 14; 12,13-diHOME, 12,13-dihydroxy-(9 Z )-octadecenoic acid; DNL, de novo lipogenesis; FABP4, fatty acid-binding protein 4; FAHFAs, fatty acid esters of hydroxy fatty acids; FFA, free fatty acid; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; GFRAL, GDNF family receptor-α-like; GLP1, glucagon-like peptide 1; IGF1, insulin-like growth factor 1; LEPR, leptin receptor; NAMPT, nicotinamide phosphoribosyltransferase; NRG4, neuregulin 4; RBP4, retinol-binding protein 4; T1DM, type 1 diabetes mellitus; TLR4, Toll-like receptor 4; WAT, white adipose tissue.
Table 2 (cont.) |^ regulation, signalling and function of adipose tissue hormones
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Palmitoleate. The first lipid that was postulated to act as an endocrine adipose lipokine was palmitoleate (16:1Δ^9 ), an abundant monounsaturated fatty acid that is mostly derived from DNL^90 (Fig. 1). Typically, the pal- mitoleate content of WAT and levels of palmitoleate in the plasma FFA pool are decreased in obese and insulin-resistant mice, owing to decreased adipose tissue DNL^8. As palmitoleate exhibits anti-inflammatory and insulin-sensitizing effects in vitro91,92^ and genetic inter- ventions that increase WAT DNL in obese mice increase systemic insulin sensitivity 90,93^ , it has been proposed that palmitoleate is a lipokine that increases metabolic health 90. Supporting this concept, dietary palmitoleate supplementation reduces atherosclerosis^92 , improves glu- cose homeostasis90,94, and suppresses liver inflammation^95 in mouse disease models. Whether a decrease in the palmitoleate content of WAT is an important step in the development of obesity-associated insulin resistance in humans is an open question. In people with obesity and insulin resist- ance, WAT palmitoleate content is not substantially altered as compared with healthy control individuals. This observation can be explained by the finding that, unlike in mice, the enzyme catalysing the final step in palmitoleate synthesis, Δ^9 -desaturase, is not downregu- lated in WAT of obese humans^96. Thus, there is no sys- temic palmitoleate deficiency in individuals with obesity and insulin resistance and, consequently, no major con- tribution to the development of cardiometabolic diseases. Nevertheless, palmitoleate is probably anti-inflammatory in humans, and supplementation might have beneficial effects in chronic inflammatory diseases.
Fatty acid esters of hydroxy fatty acids. Fatty acid esters of hydroxy fatty acids (FAHFAs) are a novel class of lipids that are linked to adipose tissue DNL 97 (Fig. 1). Genetic mouse models with suppressed DNL in multiple organs or selectively in adipocytes have decreased levels of FAHFA species (containing fatty acids derived from DNL) in adipose tissues and plasma 97,98^. In both mice and humans, WAT and plasma levels of such FAHFAs correlate with systemic and adipocyte insulin sensitiv- ity97,99. These results led to the model that the systemic decrease of the levels of WAT DNL-derived FAHFAs in obesity contributes to the development of general insulin resistance and the deterioration of metabolism. Mechanistic studies performed to provide evidence for the aforementioned model focused on positional isomers of palmitic acid hydroxystearic acid (PAHSA), which are an abundant subgroup of WAT FAHFAs^97. For example, oral gavage of 5-PAHSA or 9-PAHSA improves glucose tolerance in insulin-resistant mice97,98. At the cel- lular level, activation of the fatty acid receptor GPR increases adipocyte glucose transport. Moreover, GPR activation and the secretion of both glucagon-like pep- tide 1 and insulin from intestinal L cells and pancreatic β-cells, respectively, were identified as potential mecha- nisms mediating the beneficial metabolic effects of PAHSAs 97,100^. The effects of PAHSAs administered by oral gavage in mice on oral glucose tolerance were, how- ever, not observed by another group^101. The discrepancy might be due to differences in the lipid content of the
vehicle and the degree of insulin resistance of the mice used in the experiments102,103. Another unresolved issue is the effective concentra- tion of FAHFAs needed to activate GPR120 and GPR in vitro, which is considerably higher than the concen- tration present in mouse plasma97,98,101. Thus, the role of FAHFAs as endocrine, antidiabetic regulators remains controversial, and more research is needed, especially to identify and corroborate molecular FAHFA targets.
12,13-Dihydroxy-(9Z)-octadecenoic acid. 12,13- Dihydroxy-(9Z)-octadecenoic acid (12,13-diHOME) was identified through an unbiased lipidomic approach as a lipokine the level of which is selectively increased in the plasma of humans and mice that are exposed to cold^104 (Fig. 1). Notably, BAT was identified as the source of circulating 12,13-diHOME in mice. This conclu- sion is based on the observation that the expression of 12,13-diHOME-synthesizing enzyme, bifunctional soluble epoxide hydrolase 2, is specifically induced in BAT depots on cold exposure 104. In both mice and humans, plasma 12,13-diHOME concentration corre- lated with the volume of active BAT 104. Functionally, 12,13-diHOME boosted energy expenditure and stimu- lated fatty acid uptake in BAT, but not in other organs, probably through the fatty acid transporters CD and FATP1 (reF.^104 ). Together, these data characterize 12,13-diHOME as a BAT-derived lipokine that augments adaptive thermogenesis in a paracrine fashion. A 2018 publication found that the concentration of 12,13-diHOME is elevated in the plasma of humans and mice under conditions of moderate-intensity exercise and that 12,13-diHOME stimulates fatty acid uptake and oxi- dation in skeletal muscle 105. The study authors showed that 12,13-diHOME is primarily produced by BAT; how- ever, the factor also acts on muscle, thereby providing evidence for an endocrine action. Taken together, the findings show that 12,13-diHOME is a novel lipokine that seems to be important for providing fatty acids to organs under conditions of high energy demand, through cellular mechanisms that need to be further explored.
Adipocyte-derived exosomal microRNAs MicroRNAs (miRNAs) are regulatory non-coding RNAs that are shared between cells primarily through exosomes^106. Evidence is accumulating for a role of exosomal miRNAs secreted from WAT and BAT in metabolic regulation 107–109^ (Fig. 1). A major proportion of plasma miRNAs originate from adipose tissues, as indicated by a decrease in the levels of many miRNA species in the plasma of mice with adipocytes deficient in the miRNA-generating enzyme Dicer, which is a phenotype that can be rescued by adipose tissue trans- plantation 108. Of note, BAT transplantation reversed the plasma increase of the endocrine hormone fibro- blast growth factor 21 (FGF21) that was observed in the Dicer-deficient mice and this effect was linked to exosomal miR-99b downregulating liver Fgf21 mRNA. In patients with lipodystrophy, a greater number of miRNAs in the circulation were found to be downreg- ulated than upregulated, suggesting that adipose tis- sue is also an important source of plasma miRNAs in
Exosomes small cytosol-containing membrane vesicles that are released by one cell to be taken up by other cells and release their content, for example microrNA.
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humans 108. In healthy volunteers exosomal miR-92a is released by brown adipocytes and plasma levels inversely correlate with human BAT activity measured by meta- bolic imaging 107 , indicating the potential of plasma miRNAs as a biomarker for BAT activity. In summary, evidence suggests that WAT and BAT are an important source of exosomal miRNAs; however, more studies are needed to understand the cell biology and regulation of the secretion process, as well as to define the specific endocrine function of miRNAs in metabolism. To conclude this section, there are a number of endocrine factors that are released by white and brown adipocytes (Fig. 1). These hormones regulate systemic energy metabolism and influence the development of cardiometabolic diseases by modulating organ-specific functions (Figs 1,3).
Factors also secreted by other organs Most adipose tissue-derived regulatory secreted factors are not exclusively produced by adipocytes but are also produced in other organs or by cells of the adipose tissue stroma–vascular fraction (TABLe 1). The latter includes
endothelial cells, preadipocytes, macrophages and var- ious immune cell types that are present throughout the body. Here we describe factors for which an endocrine function has been demonstrated and that are expressed to a certain degree also outside adipose tissue. Cytokines and chemokines are not discussed, as they probably exert most or all of their functions as paracrine medi- ators. Exceptions are interleukin-6 (IL-6) and C-X-C motif chemokine ligand 14 (CXCL14), for which endo- crine roles are supported by experimental data. As the contribution of adipose tissue to the effects of the factors discussed is not self-evident, special focus will be placed on data that suggest a specific contribution of adipose tissues versus other organs as the source of the respective endocrine factor.
Adipokines also released by hepatocytes Fibroblast growth factor 21. The endocrine hormone FGF21 has attracted a lot of attention owing to its ben- eficial pharmacological action on metabolism in obese rodents and primates. In mice, both adipose tissue and brain are important target organs that mediate major metabolic effects (weight loss and decreased plasma glucose and triglyceride levels) of FGF21 administered in therapeutic doses 110–112^. The liver is the primary or only source of plasma FGF21 under basal conditions in mice as well as in humans 113,114^. The production of hepatic FGF21 is induced on prolonged fasting or pro- tein restriction, and in this context it increases hepatic gluconeogenesis, fatty acid oxidation and ketogenesis via stimulation of the hypothalamus–pituitary– adrenal axis and sympathetic tone 110,115^. Paradoxically, the production of hepatic FGF21 is also induced by carbohydrate overfeeding, and under this condition it supports the disposal of dietary glucose via acute insulin-sensitizing effects mediated through FGF receptors in adipose tissue110,116. Thus, FGF21 produced in the liver fine-tunes metabolism during both fasting and acute overfeeding by acting on brain and adipose tissue, respectively. The role of adipose tissue-derived FGF21 is more complex and controversial. FGF21 produced in adipose tissue might not be important in obesity-associated insulin resistance, as adipose tissue-specific FGF21- deficient mice that are fed a high-fat diet did not show decreased circulating FGF21 levels or insulin resistance, in contrast to liver-specific FGF21-deficient mice^114. By contrast, adipose tissue-derived FGF21 seems to be rele- vant under thermogenic stimulation. In mice exposed to cold, FGF21 expression in BAT and subcutaneous WAT is substantially increased; however, this effect usually occurs without any increase in plasma FGF21 levels116–118. A 2017 study that used tissue-specific FGF21 knock- down indicates that expression and autocrine signalling of FGF21 in adipose tissue is required for the proper development of thermogenic beige adipocytes in WAT of cold-exposed mice^119. Of note, other studies provide evidence for endo- crine roles of BAT-derived FGF21. One study reports that the severely dysfunctional BAT of UCP1-deficient mice showed a strong induction of Fgf21 expression and elevated plasma FGF21 levels, as compared with
Adiponectin, adipsin
Leptin, adiponectin, NRG4, palmitoleate, FAHFAs, 12,13-diHOME, FGF21, IGF1, CXCL14, GDF15, vaspin
Adiponectin, NRG4, palmitoleate
Leptin, adiponectin, palmitoleate, FGF21, omentin, vaspin
Protective
Protective
Protective
Protective
Detrimental
Detrimental
Detrimental
Detrimental
FABP4, RBP4, resistin, eNAMPT Context dependent IL-
Context dependent IL-
eNAMPT
FABP4, eNAMPT
Liver Resistin
β -Cell dysfunction and/or diabetes mellitus
Obesity, insulin resistance and/or diabetes diabetes mellitus
Nonalcoholic fatty liver disease
Cardiovascular disease (atherosclerosis, cardiac hypertrophy and so on)
β-Cell
Adipocyte
Blood vessel
Insulin receptor
Fig. 3 | Functional relevance of adipokines and lipokines in cardiometabolic diseases. Various adipokines and lipokines have been found to exert either protective or detrimental effects on the development of cardiometabolic diseases. Causal, disease- modifying roles of the hormones presented have been demonstrated by genetic or pharmacological intervention studies in rodents, as described in detail in the text. Of note, for most of the factors, only a limited number of proof-of concept studies have been performed. The intensively studied hormone IL-6 displayed variable, context-dependent results, which can be explained by cell type-specific modulation of inflammatory and metabolic pathways. CXCL14, C-X-C motif chemokine ligand 14; 12,13-diHOME, 12,13-dihydroxy-(9 Z )-octadecenoic acid; eNAMPT, extracellular nicotinamide phosphori- bosyltransferase; FABP4, fatty acid-binding protein 4; FAHFAs, fatty acid esters of hydroxy fatty acids; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15; IGF1, insulin-like growth factor 1; NRG4, neuregulin 4; RBP4, retinol-binding protein 4.
Nature reviews |^ Endocrinology
can also originate from Kupffer cells and other immune cells in the liver. Mouse studies using cell type-specific knockdown of IL-6RA showed variable and unanticipated results. For example, hepatocyte-specific IL-6RA-deficient mice showed systemic insulin resistance and pro- nounced hepatic inflammation, even when fed a nor- mal diet, demonstrating the anti-inflammatory effects of IL-6 in the liver 141. Similarly, myeloid cell-specific IL-6RA-deficient obese mice showed a poorer meta- bolic phenotype than obese controls associated with WAT macrophages polarized towards a proinflamma- tory M1 phenotype 142,143^. By contrast, T cell-specific or natural killer cell-specific IL-6RA deficiency improved insulin resistance in obese mice144,145. Thus, IL-6 can act in both a proinflammatory and an anti-inflammatory fashion, depending on cell type and context. Given these complex functions, it is not surprising that the role of WAT-derived IL-6 in hepatic glucose metabolism and insulin resistance is still controversial135,136.
Resistin. Resistin is a protein that is secreted from mouse adipocytes and macrophages, and its level is increased in the plasma of obese mice as compared with lean con- trols146,147. Resistin accelerates insulin resistance as well as the development of inflammatory metabolic diseases, including NASH, by acting on many cell types, includ- ing adipocytes, hepatocytes, myocytes, macrophages, endothelial cells and hypothalamic neurons^146. The pat- tern recognition receptor TLR4 mediates at least some of the proinflammatory effects of resistin^148. However, no specific receptor has been identified so far, which limits functional studies of this adipokine. Importantly, human resistin is derived from circu- lating monocytes and tissue-resident macrophages, but not adipocytes 146,149^. Nevertheless, plasma levels of the hormone also increase with obesity in humans 146. Notably, a humanized mouse model expressing human resistin exclusively in macrophages showed increased insulin resistance and inflammation as compared with control animals^150. Thus, human resistin plays a role in obesity-associated inflammation and insulin resistance, but in humans the contribution of adipose tissue to plasma resistin levels is probably less important than in mice.
Ubiquitously expressed adipokines Growth differentiation factor 15. Growth differentiation factor 15 (GDF15; also known as macrophage inhibitory cytokine 1) is a member of the transforming growth fac- tor superfamily with anti-inflammatory properties. In humans, GDF15 plasma levels are increased in many pathological conditions, including cancer, cardiovascular disease and kidney failure, and GDF15 levels are positively associated with the risk of death^151. Many organs can pro- duce GDF15 (for example, liver and skeletal muscle). However, this factor is not expressed in these organs under basal conditions and is induced only on oxidative stress, proinflammatory cytokine action or other stimuli^151. GDF15 is also secreted by preadipocytes and adipo- cytes^152 , and serum levels are increased in humans with obesity and in obese mice. As a downstream effector of the anti-inflammatory cytokines IL-4 and IL-13, in
WAT, GDF15 can prevent excessive inflammation and improve glucose metabolism 153. Studies suggest that GDF15 mediates metabolic effects by acting on the neuro- nal brainstem receptor GDNF family receptor-α-like (GFRAL) 154–156^. However, in obesity, GDF15 mRNA is increased not only in WAT but also in the liver and pos- sibly other organs^157. Thus, the contribution of adipose tissue to circulating GDF15 in this context is not clear, and overall the status of GDF15 as an endocrine adipo- kine is not well established. Nevertheless, recombinant GDF15 infusion reduces body weight and corrects many obesity-related metabolic derangements in rodent and primate models of obesity, thereby indicating therapeutic potential^157.
Nicotinamide phosphoribosyltransferase. Nicotinamide phosphoribosyltransferase (NAMPT; also known as visfatin) is a protein that functions both intracellularly and extracellularly. The extracellular function was first identified through its activity as a bone marrow-derived B cell growth factor^158. In 2005, researchers discovered that this factor is expressed in human visceral adipose tissue and renamed it ‘visfatin’ 159. In the same publica- tion, the protein was reported to have insulin-mimetic properties, which could not be confirmed, leading to the retraction of the article. The visfatin story took an unexpected turn when scientists discovered that the protein is NAMPT, which is the rate-limiting enzyme in the salvage pathway of nicotine amide dinucleotide (NAD +^ ) synthesis, thereby identifying an important intracellular function of the protein^159. As NAMPT is widely expressed, it remains unclear whether adipose tissue is an important source of circu- lating extracellular NAMPT (eNAMPT). Experiments to address this question using adipocyte-specific NAMPT-deficient mice were inconclusive owing to severe adipose tissue dysfunction in these animals 160. Nevertheless, plasma NAMPT levels are positively associated with obesity and insulin resistance in many clinical studies 159. Moreover, eNAMPT has various activities, including some that implicate it in the patho- genesis of chronic diseases such as atherosclerosis 161 and diabetes 162. Importantly, eNAMPT increases the proinflamma- tory actions of macrophages and neutrophils, boosts the activation and proliferation of lymphocytes and exerts detrimental effects on pancreatic β-cells 159,162^. Of note, although eNAMPT activates well-established signal- ling pathways related to inflammation and apoptosis, a signalling receptor has not yet been identified. It has been speculated that the enzymatic activity of eNAMPT, which regulates adenine nucleotide signalling, medi- ates the observed cellular effects 159. More intervention studies that separate intracellular functions from extra- cellular functions (for example, using inactivating anti- bodies^162 ) are needed to understand the role of eNAMPT in metabolic regulation and cardiometabolic disease.
Omentin. Omentin (also known as intelectin 1) is a lectin-like protein that is expressed in the small and large intestine, where it is involved in microbial surveillance^163. Furthermore, omentin is produced by endothelial and
Nature reviews |^ Endocrinology
other stroma–vascular cells in various organs. The name ‘omentin’ is derived from the high expression of this factor in omental (that is, visceral) WAT compared with subcutaneous human WAT^164. Notably, mice do not express appreciable amounts of omentin in adipose tis- sues, which has hampered mechanistic studies address- ing the physiological role of adipose-derived omentin^165. Observational studies have established that low omen- tin plasma levels in humans are associated with insulin resistance and a higher risk of cardiovascular disease^165. Moreover, in humans, adipose tissue production of omentin is suppressed by insulin, which explains the decrease of circulating omentin levels in hyperinsuli- naemic insulin-resistant states 166. Although no specific cell surface receptor has been identified, omentin elicits distinct downstream signalling events, which explain the beneficial metabolic effects 165 and suggest therapeutic potential.
Vaspin. Vaspin (also known as serpin A12) is an insulin-sensitizing protease inhibitor, the level of which is frequently but not always increased in the circulation of individuals with obesity 16,167^. Vaspin was originally identified as a visceral WAT-specific adipokine in dia- betic rats 167. Subsequent work showed that in humans vaspin was detectable only in WAT of individuals with obesity but was not confined to visceral WAT^168 ; vaspin was also enriched in the stroma–vascular fraction of adipose tissue 169. As vaspin is widely expressed, and no adipose tissue-specific deficient models have been reported so far, it remains unclear whether circulating vaspin is derived from adipocytes. Nevertheless, animal studies demonstrate promising beneficial roles of vaspin in diabetes and cardiovascular disease 167. Future work should focus on the mechanism of action of vaspin, which may involve inhibition of specific proteases (for example, kallikrein 7)^170. Taken together, the findings show that a large num- ber of regulatory molecules with divergent activities are secreted from adipose tissues. Most of these molecules are also produced by other organs or by other cell types in adipose tissues (TABLe 1), and in many cases the exact contribution of adipocytes needs to be established.
Therapeutic aspects Leptin-based therapies As described previously, leptin is a hormone essential for the regulation of energy metabolism and major endocrine axes. Accordingly, recombinant leptin can be used to treat endocrine dysfunctions in hypoleptinae- mic conditions that are present in extremely lean women with amenorrhoea^171 and also in patients with lipodys- trophy^172. In addition, leptin administration normalizes plasma glucose levels in rodent T1DM models that have low leptin levels 173. The mechanisms described remain unclear, but leptin may act by correcting glucagon hyper- secretion or by suppressing cortisol secretion^174 , or both. However, leptin deficiency is less pronounced in human T1DM, and leptin treatment might not be effective in patients with T1DM^174. The weight-lowering and insulin-sensitizing effects of leptin make it an attractive therapeutic approach to
tackle obesity-related metabolic dysfunction. Proving this concept, leptin treatment was found to be effective in humans with obesity caused by rare leptin loss-of- function mutations^33. However, one major hurdle in the development of leptin as a general antiobesity drug is the presence of leptin resistance in individuals with obesity and in obese rodents, where typically very high plasma levels of the hormone are present. Leptin resist- ance is a complex phenomenon that involves defects in the uptake of leptin into the cerebrospinal compartment, as well as the attenuation of leptin signalling in central neurons 175. Notably, potential approaches to overcome leptin resistance in obesity have been identified, including treatment with the islet hormone amylin176–178^ and agents that restore leptin signalling by decreasing intracellu- lar stress in central neurons^179. Although the potential adverse effects of leptin therapy, such as liver fibrosis^180 , need to be kept in mind, the leptin signalling pathway is amenable to pharmacological intervention, and leptin sensitizing may be a viable option for the treatment of common metabolic diseases.
Adiponectin-based therapies Given its pleiotropic beneficial effect in cardiometa- bolic diseases (as identified in rodent disease models), adiponectin signalling is an attractive therapeutic target. The levels of circulating adiponectin can be elevated by pharmacological intervention using PPARγ agonists. Moreover, adiponectin mediates at least part of the result- ing positive effects of PPARγ agonist treatment on insu- lin resistance, development of fatty liver and other organ disturbances, as comparisons of adiponectin-deficient and wild-type mice demonstrated 181,182^. Adiponectin receptors were also targeted directly in rodents using AdipoRon, an orally available small-molecule ADIPOR and ADIPOR2 dual agonist^183. AdipoRon administered to obese mice not only improved insulin resistance^183 but also slowed the development of inflammatory disorders such as generalized fibrosis 184 , providing proof of con- cept for adiponectin-specific therapies. A general caveat is that even though high adiponectin levels are strongly associated with insulin sensitivity and a low risk of devel- oping T2DM in humans, a causal role of adiponectin and salutary effects of high adiponectin levels on mortality could not be confirmed in large genetic studies^185. These findings cast doubt on the general translatability of the rodent data to humans, and more research is warranted to resolve this paradox.
Other adipokine-based therapies Although many adipokines and other adipose tissue hor- mones are associated with cardiometabolic diseases and are promising as biomarkers^186 , none have as yet as much therapeutic validation as leptin. Therapeutic targeting of molecules secreted from adipose tissue is generally difficult, and a potential reason for this is that many exert pleiotropic, modulatory functions. This fact is not ideal with regard to therapeutic efficacy, especially in the context of complex cardiometabolic diseases that require long-term treatment, as both pleiotropic effects and sustained dosing increase the risk of adverse effects. For example, the administration of NRG4 might exert
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Nature reviews |^ Endocrinology
