Thematic review series: Adipocyte Biology. Adipose tissue function and plasticity orchestrate nutritional adaptation

This review focuses on adipose tissue biology and introduces the concept of adipose tissue plasticity and expandability as key determinants of obesity-associated metabolic dysregulation. This concept is fundamental to our understanding of adipose tissue as a dynamic organ at the center of nutritional adaptation. Here, we summarize the current knowledge of the mechanisms by which adipose tissue can affect peripheral energy homeostasis, particularly in the context of overnutrition. Two mechanisms emerge that provide a molecular understanding for obesity-associated insulin resistance. These are a) the dysregulation of adipose tissue expandability and b) the abnormal production of adipokines. This knowledge has the potential to pave the way for novel therapeutic concepts and strategies for managing and/or correcting complications associated with obesity and the metabolic syndrome. This review focuses on adipose tissue biology and introduces the concept of adipose tissue plasticity and expandability as key determinants of obesity-associated metabolic dysregulation. This concept is fundamental to our understanding of adipose tissue as a dynamic organ at the center of nutritional adaptation. Here, we summarize the current knowledge of the mechanisms by which adipose tissue can affect peripheral energy homeostasis, particularly in the context of overnutrition. Two mechanisms emerge that provide a molecular understanding for obesity-associated insulin resistance. These are a) the dysregulation of adipose tissue expandability and b) the abnormal production of adipokines. This knowledge has the potential to pave the way for novel therapeutic concepts and strategies for managing and/or correcting complications associated with obesity and the metabolic syndrome. Although changes in adipose mass is a familiar phenomenon to most healthy individuals, it only appears to become clinically relevant when abnormal fat accumulation is associated with health problems. For example, it is well known that overweight and obese individuals have a substantially greater risk of developing chronic diseases, such as cardiovascular disease (mainly ischemic heart disease and stroke), diabetes, musculoskeletal disorders (especially osteoarthritis), and some cancers (endometrial, breast, and colon). Furthermore, childhood obesity is associated with a greater chance of premature death and disability in adulthood. Hence, it is clear that a better understanding of the mechanisms linking adipose tissue development, function, and expansion is required to improve our chances of identifying the most successful therapeutic approaches. In mammals, adipose tissue develops in many different sites throughout the body and generally occurs in areas of loose connective tissue, such as subcutaneous layers between muscle and dermis. However, adipose-specific depots also form around the heart, kidneys, and other internal organs. Recent studies indicate that the adipose tissue is not a homogeneous organ. In fact, new profiling technologies have revealed depot-specific differences in the metabolic profiles, which link depot-specific susceptibility to obesity and related disorders (e.g., intra-abdominal/visceral vs. subcutaneous) (see below). In addition, an early but popular classification of adipose tissues remains and refers not to its location but to its white or brown colorationwhite adipose tissue (WAT) and brown adipose tissue (BAT), respectively. Rodents have distinct depots to represent these two types of adipose tissue (e.g., epididymal WAT and interscapular BAT). The topographic distribution of BAT in humans is slightly different. Humans are born with BAT located mainly around the neck and large blood vessels of the thorax that it is subsequently replaced by WAT in adults. As more comparative studies are performed, it is becoming clear that additional differences exist between rodent and human adipose tissues (1.Casteilla L. Penicaud L. Cousin B. Calise D. Choosing an adipose tissue depot for sampling. Factors in selection and depot specificity.Methods Mol. Biol. 2001; 155: 1-19PubMed Google Scholar). Hence, some caution should be exercised when extrapolating information from one species to another. In addition to its roles in providing insulation and mechanical support, adipose tissues have traditionally been defined as the major sites for storage of surplus fuel. Indeed, during times of increased food intake and/or decreased energy expenditure, surplus energy is deposited efficiently in adipose tissue in the form of neutral triglycerides. This process is mediated by key lipogenic enzymes. However, when food is scarce and/or energy expenditure requirements increase, lipid reserves are released to provide fuel for energy generation. Therefore, adipocytes also contain “lipases” that break down triglycerides into glycerol and fatty acids that can then be transported in the blood to the liver, muscle, and BAT, where they are used in fatty acid oxidation (Fig. 1). There is also evidence that glycerol and FFA can be reesterified in adipocytes, thereby allowing FFA flux to be acutely regulated. Therefore, the two principal functions of WAT are to store excess energy as triglycerides, in large unilocular droplets, and to release it in the form of FFA. In contrast, BAT stores triglycerides in multilocular adipocytes as quick-access fuel for heat production through mitochondrial “uncoupling” of oxidative phosphorylation of FFA. This thermogenic process is vital in neonates exposed to the cold but may no longer be required and appears to be lost in adult humans, who have developed additional strategies to keep warm. It is unclear whether the locations of different adipose tissue depots in proximity to vital organs exert exclusively the function of mechanical support or, more likely, play a key metabolic role as a local source of emergency fuel. Nonetheless, given these functions, it is not surprising that the adipose tissue is exquisitely designed to respond to acute changes in nutritional cues. Indeed, at the molecular and biochemical levels, adipocytes are well equipped with the machinery to respond to both hormonal (e.g., insulin) and sympathetic (e.g., adrenergic) stimulation. In 1994, the discovery of leptin, a satiety factor produced predominantly by adipose tissue, added a further dimension to our understanding of adipose tissue function (2.Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (11807) Google Scholar). It demonstrated that this tissue was capable of emitting signals to regulate food intake and energy expenditure and thereby to orchestrate changes in energy balance and whole body nutritional status. Subsequent advances have identified many more adipose-derived secreted products (Table 1), which together with electron microscopic evaluations have reinforced this notion and led to the reclassification of adipose tissue as an endocrine organ. An important aspect of adipose tissue endocrinology is the recognition that numerous other cell types, in addition to adipocytes, are also present and play important roles in regulating adipose tissue function. The additional cell types present in the adipose tissue or its stroma-vascular fraction include pericytes and endothelial cells, monocytes, macrophages, and pluripotent stem cells (including preadipocytes). Interestingly, these nonadipocyte cells may also be the main source of some secreted factors.TABLE 1.Factors secreted by adipose tissueLipid metabolismLipoprotein lipase (LPL), free fatty acids, glycerol, apolipoprotein ESteroid hormonesEstrone, estradiol, testosteroneGrowth factors and cytokinesIGF-1, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), leptin, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6)Vasoactive factorsMonobutyrin, angiotensinogen angiotensin II, atrial natriuretic peptideEicosanoidsProstaglandins E2 (PGE2), prostaglandins F2a (PGF2a), prostacyclin (prostaglandin I2/PGI2)Complement systemFactor B, factor C, C3, C1q, factor D adipsin/acylation-stimulating protein (ASP/C3desARg)Binding proteinsRetinol BP, IGF-BPs, sTNFRsExtracellular matrix proteinsMonocyte chemotactic protein-1 (MCP-1)OthersAdiponectin (Acrp30/AdipoQ), cholesteryl ester transfer protein, plasminogen activator inhibitor 1, haptoglobin, LPA, lysophosphatidic acid, resistin, visfatin/PBEF, omentin, fasting-induced adipose factor, metallothionen, apelinAdapted from Ref. 45.Vernon R.G. Denis R.G. Sorensen A. Signals of adiposity.Domest. Anim. Endocrinol. 2001; 21: 197-214Crossref PubMed Scopus (54) Google Scholar. BP, binding protein; IGF-BPs, insulin-like growth factor binding proteins; LPA, lysohosphatidic acid; PBEF, pre-B-cell colony-enhancing factor; sTNFRs, soluble tumor necrosis factor receptors. Open table in a new tab Adapted from Ref. 45.Vernon R.G. Denis R.G. Sorensen A. Signals of adiposity.Domest. Anim. Endocrinol. 2001; 21: 197-214Crossref PubMed Scopus (54) Google Scholar. BP, binding protein; IGF-BPs, insulin-like growth factor binding proteins; LPA, lysohosphatidic acid; PBEF, pre-B-cell colony-enhancing factor; sTNFRs, soluble tumor necrosis factor receptors. Adipose tissue-derived secreted factors (particularly from WAT depots) can have effects on multiple biological systems, including energy homeostasis (lipid and carbohydrate metabolism, appetite, thermogenesis), the immune system, reproductive function, hemostasia, blood pressure, and angiogenesis (Table 1). As discussed below, some of these actions underscore the links between obesity and its related pathologies, such as insulin resistance, hypertension, hyperlipidemia, diabetes, and heart In adipose tissue and expansion is by the actions of a of factors that together form a and designed to energy These factors include a of and Although some of these factors may be relevant to adipose tissue development, most a of energy balance by and/or energy This is a for the of However, the of obesity also a healthy adipose tissue to the storage from the energy Hence, understanding the role of adipose tissue biology in an of whole body energy Indeed, an in metabolic disease is the of signals that this aspect has been to The of and has been further by the of in This has it to of cells from and Nonetheless, a of strategies have to or cell that can be to in These have the to and the mechanisms that regulate are to two that this in some from the Mol. Biol. PubMed Scopus Google of PubMed Scopus Google Scholar). In the most aspect of is the of that (Fig. The are and binding protein both of which are required to the of (e.g., M. M. The gene in and in Biol. PubMed Scopus Google Scholar). These the of adipocytes can be further by additional such as binding protein However, the process of is more as by the of novel of For our have identified and new factors such as M. D. M. is an inhibitor of and a of early Biol. PubMed Scopus Google and that to of M. A. of the factor in human and Biol. PubMed Scopus Google as well as such as M. M. A. The and its are during early human PubMed Scopus Google and M. A. the of obesity and insulin PubMed Scopus Google Scholar). These are of a of factors to or in (Table layers of in the not only from the of factors but from the to a of and that the of This that expansion of adipose tissue is not a process to an excess of but is an that is and of in in factor fatty in factor growth factor; insulin-like growth factor binding protein; growth factor; growth in Open table in a new tab growth factor; insulin-like growth factor binding protein; growth factor; growth An of the is by the role by the which was in and of the of by PubMed Scopus Google L. of during Biol. PubMed Scopus Google Scholar). our we have also demonstrated that the and its and are during early of human in this in and M. M. A. The and its are during early human PubMed Scopus Google Scholar). have also demonstrated that accumulation of is a for the of in the A. of to different PubMed Scopus Google Scholar). These studies that a of signals occurs at both the cell and in Furthermore, we have that between tumor necrosis factor-α and both of which can and necrosis a of Scholar). Therefore, it appears that which are increased in may mechanisms to and necrosis a of Scholar). some of these mechanisms may be relevant to human obesity is by the role by in human adipose tissue A. M. in human PubMed Scopus Google this fact, species differences also exist between the mouse and human M. M. A. The and its are during early human PubMed Scopus Google Scholar). In of the of excess adipose tissue mass is to be for obesity-associated peripheral insulin and metabolic This is by the of a of rodent of peripheral insulin by of adipose tissue such as Y. of insulin in Biol. PubMed Scopus Google Scholar). Indeed, the of adipose depots peripheral insulin through and is of the metabolic associated with disorders in These studies the important for a lipid storage organ in the of nutritional a of no one with the concept that obesity is the of a between food intake and energy is is the concept that the expansion of the adipose tissue and its storage may be or The is that adipose tissue should be to to excess of However, in we have that the process of adipose tissue expansion the form of the of new adipocytes and the growth of is a process that the current of the adipose tissue as a whole has been more to to an of Therefore, it is not surprising that that to the storage of the adipose tissue to with the In addition to lipid adipose tissue also an important in This was demonstrated by metabolic of the adipose-specific Here, of in adipocytes was to peripheral insulin and but in adipose tissue Although the molecular for this remains it is clear that into adipose tissue a role in and in whole body carbohydrate and in the of homeostasis and metabolic PubMed Scopus Google Scholar). other rodent with when with nutritional can obesity but are from the associated metabolic dysregulation resistance, diabetes, fatty and L. The role of fatty acid binding in metabolic and PubMed Scopus Google and in fatty protein and Endocrinol. PubMed Scopus Google Adipose tissue-derived on health and PubMed Scopus Google Scholar). These have further the understanding that both adipose tissue and adipose function the mechanisms linking obesity to insulin resistance. Two are that provide a molecular understanding of insulin resistance. in the of a nutritional is a to surplus This in of that in other such as and This accumulation the metabolic or of this The that nutritional on the adipose tissue and/or changes in These then as of insulin and to both local and insulin resistance. review and the and distinct that are when the adipose tissue expandability a factor and be in the These are other such as muscle, liver, heart, or These tissues are not designed to store large of and are more to the effects of excess fat Although the of the nutritional to these organs may be the to these species is to the organ. susceptibility may also be by the In our the and chronic of and lipid may in a metabolic in organs such as muscle and liver, to and fatty acids The of the to a organ on main a) the and of the excess of b) the of the mechanisms of and storage of fatty acids into the and the oxidative of the organ. It is that the greater the of the more the However, not organ be The of the of fatty acids in organs may the of and fatty acids to the In this factors such as may as a in muscle and other peripheral organs. of in these tissues may the of triglycerides but in the may the accumulation of more fatty and with and/or in the context of we should of to respond to the excess of For we have that an factor is to adipose tissue, can be in or muscle of excess L. M. M. M. by adipose tissue expandability and peripheral lipid of 1, Scholar). of in these organs the and storage of fatty acids, but this storage not to Therefore, it is not only the excess of but the storage that the of The factor to be is whether the oxidative of the organ is to clear the excess of For the are and we have that that in are also associated with the that is in of overnutrition. Therefore, a of these the and of to regulate and new potential therapeutic (see below). There is the of lipid species that it has been that accumulation of triglycerides in and muscle was a of related to insulin resistance. However, our indicate that of triglycerides may not be the of L. M. M. M. by adipose tissue expandability and peripheral lipid of 1, Scholar). we the accumulation of triglycerides in peripheral organs of energy balance to the of the organ. that in is a between the in triglycerides and lipid species L. A. M. strategies for of obesity related Biol. PubMed Scopus Google Scholar). In this triglycerides may be a of excess the Although it may be to to our that strategies to may a more by the accumulation of other more lipid species L. M. M. M. by adipose tissue expandability and peripheral lipid of 1, Scholar). This is in the of in of L. M. M. M. by adipose tissue expandability and peripheral lipid of 1, Scholar). of triglycerides in the context of energy balance a of insulin and a metabolic The of insulin have also been the of and provide to the of the lipid In the from are for insulin and diabetes, particularly in obesity and Indeed, lipid in and from the M. fatty acids and of Endocrinol. PubMed Scopus Google and increased insulin from cells, through mechanisms in the of and PubMed Google Scholar). In adipose tissue and muscle, increased insulin and The a by which led to However, this has been and an mechanisms of insulin PubMed Scopus Google Scholar). Here, is to in lipid and to the of such as and These then that are and/or The include such as and such as and Hence, can a in In with we demonstrated that phosphorylation of a in can be by the ester and of the This of and its function in insulin this is not by R. A. of insulin by protein role of Endocrinol. PubMed Scopus Google Scholar). However, in studies the role of increased in insulin resistance, we provide evidence that such as are to be important of insulin resistance. Indeed, by the of a key in the of we can insulin in numerous of obesity increased R. A. A. M. M. of insulin of Scholar). Although some evidence in A. M. Y. in the of insulin Biol. PubMed Scopus Google A. M. A. M. insulin in PubMed Scopus Google should the and mechanisms by which insulin resistance. The relevant of adipose tissue to nutritional is to The refers to a secreted protein from adipose tissue production is in obese and may affect obesity-associated metabolic has on the endocrine actions of these particularly with to roles in regulating whole body homeostasis (Table we have the current information in and we to that this aspect of in some Adipose tissue-derived on health and PubMed Scopus Google as of energy balance and PubMed Scopus Google R. effects of adipose tissue on cells in the of Scopus Google Scholar). However, a aspect of is potential to regulating adipose tissue development, and/or Indeed, many of the that are in insulin can also affect lipid and thereby to fat distribution (Table Therefore, in addition to endocrine actions on food intake and/or energy expenditure, are to or effects that can adipose tissue functions and further WAT For these it is clear that production and are not mechanisms in insulin resistance. However, one aspect that may the two mechanisms is the that are to play a role in to in nutritional status. These are then and/or no longer in the of overnutrition. In contrast, is associated with (Fig. effects of on on or in and/or and insulin insulin in muscle and lipid of insulin release by and insulin may have a role in in may the on food but to increased energy present in human insulin insulin to no at on insulin and in healthy but may improve insulin in insulin in no in healthy humans with by white adipose tissue and multiple mechanisms include phosphorylation of and of including and and effects in from insulin to in role in obesity may play a role in the of in the of obesity in not insulin by of insulin at in by of both and with to in obesity may play a role in in that of in the of in and present in human insulin but not as as on insulin in insulin is insulin in muscle not insulin role in as is increased with not signals and but not protein fat of Open table in a new tab effects of on lipid and in of in muscle and in in adipose in the sympathetic evidence of on food but to increased energy present in human in muscle and in adipocytes in muscle increased into and in BAT function and BAT and of fatty acid and with fat oxidation adipose tissue of fatty acid and present in human fatty acid and in muscle in and in in may be in not in human brown adipose Open table in a new tab protein fat of BAT, brown adipose play an important role in both and energy In the but chronic in production in adipose tissue can have a on whole body energy balance and metabolic PubMed Scopus Google and insulin PubMed Scopus Google Scholar). The of the on insulin is well The role of in Biol. PubMed Scopus Google (Table However, also lipid in adipocytes, and BAT function and necrosis a of The role of in Biol. PubMed Scopus Google L. of functions in cell and PubMed Scopus Google L. A. necrosis factor of brown adipocytes and brown function in PubMed Scopus Google Scholar). of these actions are mediated by the 1, that some and necrosis a of L. of functions in cell and PubMed Scopus Google tumor necrosis factor by Biol. PubMed Scopus Google Scholar). these actions adipose tissue expandability and its lipid storage In this local in adipose tissue can to obesity-associated and in other such as muscle, liver, and can regulate the production of other (including leptin, and other and thereby further and/or its effects on peripheral organs. the actions are for for remains to be (Table not have a role in insulin and PubMed Scopus Google Scholar). Nonetheless, in the between the immune and adipose tissue biology appears to be a surplus fuel can be for by immune cells during and/or As with other that insulin (e.g., resistin, are also increased in obese and affect lipid flux J.M. L. binding protein to insulin in obesity and PubMed Scopus Google The current biology of PubMed Scopus Google Scholar). that these are to and and/or to adipose In they adipose tissue expandability and thereby to lipid In with an that may play a role in body fat distribution L. M. M. M. D. M. and M. A. protein is associated with insulin and body fat distribution in Endocrinol. of and fat A. M. A. and protein is associated with but not with or fat in of Scholar). Furthermore, is to and actions A. human in human adipocytes, mouse adipose and PubMed Scopus Google Scholar). The actions of the such as and leptin, are also relevant to adipose tissue function and they can accumulation and adipose In addition, peripheral fuel expenditure in muscle and tissues from (Table However, in obese the of both and are through decreased or decreased Hence, in tissues adipose expansion is the has been to have lipogenic it has a potential role in regulating lipid an relevant to metabolic PubMed Scopus Google A. the link between obesity and Mol. PubMed Scopus Google Scholar). the and that is a major in obesity-associated metabolic we therapeutic The most be to the excess of in the through strategies at food energy expenditure, or, more by the of through such as the However, to these have been in most Hence, other strategies to the effects of are These may include the of adipose tissue and other organs by the of neutral triglycerides of more lipid This may be at the of the adipose tissue by and the of of adipose In fact, this is through the of of the factor it is that strategies at the between growth and the of new adipocytes have the added of some metabolic However, the most be to the of adipose tissue and/or other organs through its into potential be the of lipid to organs with increased to with surplus However, for this to be it be to substantially our knowledge of lipid metabolic in organs and The from these is that it is that the of obesity a of energy the for expansion of the adipose tissue is that the of obesity and associated In fact, it be that it may not be the of fat but the between energy surplus and storage and the of the surplus of energy in tissue that be the main of metabolic The are to and present of who have to the studies to in this The for the of many relevant to is by the and the and the on and Adipose tissue and functions in the