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Home , Adipose tissue

International Journal of (2000) 24, Suppl 4, S20±S22 ß 2000 Macmillan Publishers Ltd All rights reserved 0307±0565/00 $15.00 www.nature.com/ijo growth and differentiation: view from the chair

DCW Lau1*

1Julia McFarlane Research Centre and Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, Canada

Obesity, the most prevalent nutritional disorder in the secretory that releases an ever increasing world, is characterized by an increase in mass. The number of bioactive mediators that act via endocrine, increasing prevalence and the associated metabolic paracrine, autocrine and=or juxatacrine modes of comorbidities of obesity in af¯uent societies, coupled action in¯uencing and carbohydrate , with the recalcitrance to successful treatment, have and overall energy . A signi®cant discov- increasingly focused the need for newer treatment ery that fueled the excitement in obesity research is approaches based on a better understanding of the that of , a fat-cell speci®c that func- pathophysiology of obesity. When intake chroni- tions as a signaling molecule on the brain to complete cally exceeds energy expenditure, most of the surfeit the negative feedback loop of the lipostatic theory of of energy is stored in the form of triacylglycerols in weight control. The third era of adipose cell biology adipose tissue. Expansion of adipose tissue mass can research, focused on the transcriptional control of fat be accomplished by an increase in the cell size, cell cell differentiation and , has greatly number or both. Mild obesity (WHO class 1 and class facilitated our understanding of the fundamental pro- 2 obesity) is typically associated with increased adi- cesses involved in fat cell development and growth, pocyte size (hypertrophic obesity), whereas more and brings hope for future discoveries that may yield severe forms of obesity in animals and therapeutic bene®ts. (class 3 obesity) are accompanied by both an increase Several transcription factors are signi®cantly in fat cell size and number (hyperplastic obesity). increased during preadipocyte differentiation and all often involves hyperpla- are involved in regulating adipogenesis. The ®rst, sia and appears to be more refractory to treatment. peroxisome proliferator activated -g is associated with a decrease in fat cell (PPARg), is a member of the nuclear hormone recep- size through mobilization of triacylglycerols or lipo- tor superfamily that heterodimerizes with retinoid X lysis. Whether there is also a reduction in the cell receptor, another nuclear hormone receptor. PPARg-2 number observed with weight loss, and whether or not is the predominant isoform found in fat cells. The there is reversion of mature fat cells to the immature second transcription factor belongs to the basic-leu- phenotypes, is unclear. cine zipper family of CAAT=enhancing binding pro- The past three decades of adipose cell biology teins (C=EBPs), for which there are six isoforms. research have witnessed three important eras of dis- C=EBPb and C=EBPd are expressed early and may covery. The ®rst era was marked by the discovery and function as early transcription activators, augmenting identi®cation of preadipocytes, and the elaboration of C=EBPa and PPARg expression in the sequence of propagating cell cultures in the seventies. Studies on events leading to adipocyte differentiation. Targeted 3T3 fatty ®broblasts and preadipocytes from rodents genetic disruption of C=EBPa and PPARg expression and humans have enabled us to increasingly recognize can result in dramatic reduction in the lipid content the pivotal role of preadipocyte proliferation and and mass of adipose tissue. A Pro114Gln in differentiation in contributing to the formation of PPARg accelerates adipocyte differentiation and has new mature fat cells. The second era coincided with been reported in a small number of patients with the advances in cellular and molecular biology, which obesity and resistance, whereas Pro12Ala began in the late seventies and mid-eighties. We polymorphism decreases receptor activity and is witnessed an explosion of data af®rming that adipose linked to lower . The cooperative tissue is no longer viewed as a passive reservoir for and possibly synergistic interactions between C=EBPa energy storage, but rather one of the most metaboli- and PPARg have been described in in vitro and in vivo cally active organs in the body. Adipose tissue is a studies, suggesting a relevant physiologic role for these transcription factors during adipocyte differen- tiation. The third transcription factor, adipocyte deter- mination and differentiation factor-1 (ADD1), also *Correspondence: DCW Lau, Julia McFarlane Diabetes Research known as steroid binding protein-1c (SREBP1c), is a Centre, Room 2501, Health Sciences Centre, 3330 Hospital Drive NW, Calgary AB, Canada T2N 4N1. member of the basic helix ± loop ± helix family of E-mail: [email protected] transcription factors. ADD1=SREBP1c appears to Adipose tissue growth and differentiation DCW Lau S21 promote adipogenesis by augmenting the transcrip- Marc Reitman and colleagues created a transgenic tional activity of PPARg, as well as inducing differ- mouse model, which has virtually no visible white fat. entiation-dependent lipogenic enzymes, such as fatty These A-ZIP=F-1 transgenic mice develop hypergly- acid synthase and lipase. cemia and compensatory and dis- Meanwhile, exciting research on the genetics of play marked , hypertriglyceridemia, obesity has taught us that, unlike animal models of elevated plasma levels of free fatty acids, and hepatic obesity, where a number of monogenic . The mass of these mice have been elegantly elucidated, including the discov- was reduced by over 95% at birth, yet brown adipose ery of leptin and leptin receptor de®ciencies in obese tissue was present and appeared normal quantitatively rodents, only about 30 ± 40% of the variance in body and morphologically. The A-ZIP=F-1 mice without fat fat mass in humans can be ascribed to genetic factors. adapt to by rapidly developing torpor, a While the precise cellular signals regulating adipo- hibernation-like state, to minimize energy expendi- genesis are beginning to become unraveled, many ture. Transplantation of white adipose tissue progres- more unanswered questions remain. The ®rst session sively reversed the metabolic and pathophysiologic of this symposium reviewed and addressed different abnormalities in the A-ZIP=F-1 mice, linking a lack of aspects of the cellular and molecular control of adipose tissue to the development of insulin resis- adipogenesis. tance, comparable to some forms of lipoatrophic Intensive investigations to date have focused on the diabetes in humans. Leptin, in contrast to the aP2- elucidation of endocrine, paracrine, autocrine and SREBP-1c transgenic mouse, failed to restore the juxtacrine factors leading to expansion of adipose diabetes in these transgenic mice, suggesting that tissue mass. Little, however, is known on cellular leptin de®ciency was not the cause but might con- mechanisms responsible for the contraction of adipose tribute to the insulin resistance present in this mouse tissue mass that occurs during negative energy bal- model. An exciting application of this novel animal ance resulting in weight loss. In the ®rst paper, model of lipoatrophic diabetes is the elucidation of the Alexander Sorisky introduced the emerging concept pathophysiology of adipose tissue homeostasis of a potential role for apoptosis in contraction of through reconstitution of fat tissue by transplantation adipose tissue mass. Apoptosis, or programmed cell of different fat-tissue-speci®c knockouts into the A- death, ®rst described in fat tissue explants, has ZIP=F-1 mice. been con®rmed in cell culture studies using 3T3, Bruce Spiegelman reviewed the transcriptional con- rodent and human preadipocytes. The , trol of differentiation in white and brown . -a (TNFa), which is known to Emerging and compelling data, mainly from his and induce apoptosis in a variety of cell types, also other laboratories, suggest that both C=EBPa and induces apoptosis in preadipocytes and this effect PPARg-2 interact synergistically and actively partici- appears to be depot-speci®c. pate in fat cell differentiation. For example, transgenic Data from Sorisky's laboratory demonstrated that the animals with selective knockouts for C=EBPa, susceptibility of fat cells to apoptosis induction is C=EBPb and C=EBPd combination, and PPARg, differentiation-dependent, with preadipocytes acquiring have greatly reduced body fat. Ligand activation of progressive resistance to apoptosis as they mature. PPARg also stimulates adipogenesis in vitro and in The expression of two anti-apoptotic proteins, bcl-2 vivo. While C=EBPb and C=EBPd induce the expres- and NAIP, a new member of a family of mammalian sion of PPARg, activation of PPARg can also turn on inhibitors of apoptosis (IAP), was found to be sig- C=EBPa expression. C=EBPa appears to be required ni®cantly increased with differentiating 3T3 fatty to maintain PPARg expression as well as regulating ®broblasts and rodent preadipocytes. Sorisky also insulin-dependent transport. C=EBPa and discussed the signaling pathways involved in apopto- PPARg are also involved in the differentiation of sis and cell survival, and how the two pathways might brown adipocytes. Brown adipocytes differ from be coordinately regulated in fat cells. Further studies white adipocytes by the presence of abundant mito- will ascertain whether or not mature adipocytes resist chondria and the mitochondrial uncoupling protein or undergo apoptosis, and the potential role of apop- (UCP-1), which is involved in respiration and thermo- tosis in affecting adipose tissue cellularity and mass. genesis. Spiegelman and colleagues recently identi®ed Hence, negative energy balance or weight loss can a PPARg-interacting protein, PGC-1, a co-activator result in a reduction in adipocyte size by depletion of which is selectively expressed in brown but not white intracellular triacylglycerols content through hor- adipocytes. PGC-1 is cold inducible and may play a mone-stimulated , reversion to immature phe- role in adaptive . Ectopic expression of notype, and possibly by decreased cell number PGC-1 in white fat and muscle cells induces expres- through apoptosis. sion of UCPs, increased respiration and mitochondrial The next two papers dealt with transcriptional biogenesis, raising the tantalizing possibility that control of adipogenesis. By selectively expressing in PGC-1 might be responsible for the commitment of adipose tissue a dominant negative protein that het- fat cell precursors to become brown adipocytes. PGC- erodimerized with and inactivated members of the 1 may induce mitochondrial biogenesis by augment- C=EBP and JUN family of ZIP transcription factors, ing the activity of NRF-1 and NRF-2, both of which

International Journal of Obesity Adipose tissue growth and differentiation DCW Lau S22 bind to and regulate the promoters of several genes not well understood. Sul and her colleagues have now encoding mitochondrial proteins. Spiegelman specu- adduced evidence that dexamethasone, a synthetic lated that PGC-1 might play a role in determining the glucocortoticoid, is a potent inhibitor of pref-1 expres- switch between white and brown adipocytes, and sion. Pref-1, a 50 kDa membrane-associated protein of increasing PGC-1 activity might become a potential 385 amino acids with six tandem EGF-repeats in the mechanism for energy dissipation and therapeutic extracellular domain, was originally cloned by differ- target for weight loss. Further studies on the expression ential screening by Sul and shown to inhibit differ- in white fat and targeted gene disruption of PGC-1, and entiation of 3T3-L1 cells. Pref-1 is highly expressed in other yet to be discovered transcriptional activators preadipocytes but its expression is down-regulated and co-activators, will help clarify many unanswered with maturation and is barely detected in mature fat questions on the transcriptional control of adipogenesis. cells. Since dexamethasone-suppression of pref-1 and The next paper by Vicent GigueÁre highlighted the transfected antisense pref-1 expression augment adi- potential role of another class of orphan nuclear pogenesis, pref-1 appears to function either as an receptors that might play a role in fat metabolism. inhibitor of adipose cell differentiation, or to maintain The -related receptors (ERRs) display signif- preadipocytes in the undifferentiated state by yet icant homology to the estrogen receptors (ERs), yet unde®ned mechanisms. Sul also provided information they do not bind estrogen and its derivatives in vitro that the juxtacrine or paracrine mode of action of pref- nor respond to them in co-transfection assays. The 1 is largely dependent on its isoforms generated via crystal structure reveals that the amino acid residues alternative splicing. What is also intriguing is the critical for the recognition of are conserved preliminary data presented to suggest that constitutive between members of the estrogen receptor and ERR pref-1 expression may be an early event that precedes families, suggesting that ER and ERR ligands are an increase in C=EBPa and PPARg expression. structurally similar. The ERR subfamily of receptors Attenuation of the pref-1 signaling may be a prere- comprises 3 closely related members, ERRa, ERRb, quisite for inducing adipose cell differentiation. Stu- and ERRl. ERRa knockout mice revealed intrauterine dies on the cell ± cell communication and cell ± matrix growth retardation and abnormal adult body composi- interaction between pref-1 and various hormonal and tion; they otherwise developed normally with normal growth factors, and the elucidation of pref-1 receptors, reproductive function. Since ERRa is highly will provide further insights into the complex extra- expressed in tissues that demonstrate a capacity for cellular and intracellular pathways controlling adipo- oxidation or activation, and that it exerts genesis. transcriptional control of the expression of medium- The speakers in this session have elegantly updated chain acyl CoA dehydrogenase in vitro, a role for the readers with some of the key advances in adipose ERRa in regulating energy metabolism in vivo could cell biology knowledge. Studies to date have enabled be envisioned. The ®ndings that ERRa null mice have us to construct a working model of the major pro- hypertrophied fat cells and abnormal triacylglycerol cesses involved in the positive and negative control synthesis in the gut and are in keeping with such of preadipocyte differentiation and proliferation. a potential role for ERRa in fat and energy metabo- Another important bene®t of adipose cell biology lism. It follows from Dr GigueÁre's talk that an ever- research is the insight into the role of fat in the increasing list of known and undiscovered orphan development of insulin resistance and the metabolic nuclear receptors, such as ERRa, and their ligands, comorbidities that compromise the health of the obese may constitute excellent targets for control of adipose state. It is likely that many more endocrine, novel tissue development and growth. paracrine, autocrine and juxtacrine fat cell-derived The ®nal paper of the session, presented by Hei- growth factors await discovery to complete our under- Sook Sul, addressed the role of a novel protein standing of the complex and dynamic interactions secreted by preadipocytes, preadipocyte factor-1 occurring in adipose tissue that eventually determine (pref-1), which exerts negative control of adipogen- body fat mass and cellularity. Future work will con- esis. Under normal cell culture conditions, 3T3-L1 tinue to unravel the fundamental processes involved in ®broblasts and preadipocytes can be induced to the transcriptional control and the cascade of intra- undergo maturation by enrichment of the culture cellular signaling pathways regulating adipogenesis. medium with and substrates. After several The next steps will probably focus on the identi®ca- rounds of cell division to reach monolayer con¯uence, tion of the mesenchymal stem cells and early pre- preadipocytes exit from the cell cycle with growth cursors that are destined to become adipocytes. arrest. Differentiation requires not only cell cycling Whether white and brown adipocytes are derived arrest and expression of speci®c transcription factors, from the same precursors and whether these cells but also a proper environment to can be transformed into one another will be of great transduce the external signals to the nucleus via a interest. The search for the magic bullet to treat and cascade of intracellular signaling steps. The classical prevent obesity will continue to fuel excitement in hormonal cocktail used for differentiation induction adipose cell biology research in the hope that future includes and insulin, but the precise discoveries will translate into therapeutic bene®ts. cellular mechanisms for differentiation induction are

International Journal of Obesity