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The Adipocyte: A Multifunctional Cell
(2006, NS 134)
Organizers: Sven Enerbäck, Alex Bailey, Anna Cederberg, Fredrik Frick
August 6-9, Thorskogs slott, Göteborg, Sweden

The beautiful Thorskogs castle just north of Göteborg on the Swedish west coast was the venue for the 134th Nobel Symposium entitled, "The adipocyte: a multifunctional cell." For three splendid summer days, some 50 scientists working on various aspects of adipocyte biology convened under the auspices of the Nobel Foundation.

Advances over the last two decades in our understanding of the adipocyte have clarified its role as a key regulator of both energy balance and intermediary metabolism. It is now known that in addition to being an insulator and energy depot, the adipocyte is a highly active cell, secreting a wealth of factors, including leptin, that play a part in CNS and appetite regulation. There is also a much greater understanding of how fat cells themselves develop from precursor cells, utilizing the nuclear receptor PPAR-y, which is also the receptor for the anti-diabetic thiazolidinedione drugs.

Despite this new information, effective treatments for obesity and its related diseases have not been developed as quickly as we had hoped. Therefore, one of the goals of this meeting was to highlight new potential targets in adipocyte biology for therapeutic intervention for the treatment of obesity and related disorders. The focus of the meeting was therefore on projects with the potential to deliver new drug targets such as: white versus brown adipocyte differentiation, adipocyte metabolism and inflammation.

The adipocyte and human health

Obesity has escalated in many regions of the world to epidemic proportions: more than 1.1 billion people are estimated to be overweight, of which 320 million are now considered obese. Findings related to obesity from the WHO, cited by Paul Zimmet (International Diabetes Institute, Australia) indicate that type 2 diabetes and cardiovascular disease cause twice the number of deaths caused by infectious disease, maternal/perinatal conditions and malnutrition combined. If no action is taken, obesity will lead to the death of 338 million worldwide, mainly from chronic diseases like diabetes and cardiovascular disorders.

Obesity is very strongly linked to type 2 diabetes. This has led to the term "diabesity" to best describe the epidemic. The number of people with diabetes will almost double over one generation from the present 190 million to 335 million in 2025. Another alarming fact is that 10-15% of children in developed nations are now overweight or obese. Thus a new generation will enter adulthood with an unprecedented level of obesity.

Allelic variations and mutations are important in how we respond to a hypercaloric environment. In his Keynote Address, in memory of the late Per Björntorp, Steve O’Rahilly (University of Cambridge, UK) discussed disease linked mutations and their pathogenic relevance. Most monogenic forms of obesity are rare; for instance only eight families with congenital leptin deficiency have so far been identified, as well as a limited number of disease-causing mutations in the leptin receptor. However, in a select population with childhood onset massive obesity, mutations in the melanocortin-4 receptor (MC4R) are found at approximately 5.5%. In the general UK population the number is 1/1000; this frequency is by far greater than that of Cystic Fibrosis.

Adipocyte differentiation

Even though we have learned a lot during the past decades regarding adipogenesis, most of this new information has dealt with rather late steps of adipogeneis (e.g. factors important for lipid accumulation like C/EBPs and PPARy); very little is known about the earliest commitment to the adipose lineage. Undifferentiated mesenchyme has the capacity to mature into brown and white adipocytes. While the exact nature of this process remains obscure, increasing data suggest that Wnt-signaling is involved. Experiments in cultured cells show that some Wnts stimulate adipogenesis while others, such as Wnt10b, block preadipocyte formation and shift cell fate towards the osteoblast lineage (Ormond MacDougald, University of Michigan, USA). In this process SFRP5 signals from mature adipocytes to stimulate recruitment of more adipocytes. BMP4 also can act in a stimulatory molecule on recruitment of preadipocytes, as well as in general PKA signaling (Daniel Lane, Johns Hopkins, USA and Karsten Kristiansen, University of Southern Denmark). During the later phase of differentiation a new subdomain of the PPAR g molecule, located within helix 7 and 8 of the ligand-binding domain, might contribute to fine-tuning of lipid synthesis within the adipocyte. Mutations in this region K365R and F372A attenuate lipid accumulation in Swiss fibroblasts while the response to TZD remains unaltered (Steve Farmer, Boston University, USA).

Brown adipocytes are present in human adipose tissue under normal conditions and are known to expand in response to adrenergic stimuli, such as in patients with pheochromocytoma. These patients display an expansion of ucp1 positive brown adipocyte tissue (BAT) cells; mitochondrial uncoupling via UCP-1 likely contributes to the lean phenotype typically observed. Thus, BAT is normally present and can most likely be induced and function in the context of human adaptive thermogenesis. Promoting brown fat differentiation is therefore a potentially a very attractive way to counteract both diet-induced and genetically acquired obesity. How white versus brown adipocytes differentiation is regulated is thus probably the most important feature of early adipocyte commitment. Harnessing the processes that enhance brown fat differentiation and increase energy expenditure could lead to effective therapies. In mature human adipocytes, forced expression of PGC1 alpha induces a brown fat-like phenotype including induction of ucp1 and other mitochondrial genes (Dominique Langin, INSERM, Toulouse, France). However, the response of typical white adipocyte PPAR y targets to PPAR y agonists is not altered by PGC1 alpha. While this reveals a high degree of plasticity in the mature white fat cell phenotype it also argues in favor of differences in early lineage specificity as the underlying mechanism in differentiation of bona fide brown adipocytes. Thus, white adipocytes can attain many typical BAT features but still maintain a white adipocyte phenotype. Induction of PGC1 alpha in white adipocytes could be a way to induce mitochondrogenesis and a capacity to convert excess energy depots to heat. Bruce Spiegelman (Harvard, USA) reviewed the evidence that PPAR-y, supported by the C/EBP proteins, is the fundamental pathway driving fat cell differentiation. Spiegelman also introduced an interesting new regulator of lineage selection. When expressed together with PPAR-y in fibroblastic cells, prdm16 is capable of inducing most, if not all, aspects of brown fat cell differentiation, including induction of ucp1. Activation of this factor could prove to be the branching point in early cell fate determination between white and brown adipogenesis. Here also the brown fat related forkhead transcription factor FOXC2 was discussed as a possible downstream target of prdm16 and as a upstream regulator of PGC1 alpha. Thus, activation of prdm16 could prove to favor expansion of the brown adipose tissue compartment. C. Ronald Kahn (Joslin Diabetes Center, USA) proposed that early cell fate decisions regarding brown vs. white fat cell precursor lineage selection might involve expression of Necdin, RIP140 and Prdm16. Based on differences in gene expression profiles among various white fat depots, certain developmental genes e.g. HoxA5, Tbx15 and Glypican, Kahn suggested that there might be distinct classes of white adipocytes that would, in a selective manner, populate the different adipose tissue depots. It is well known that in rodents the interscapular brown fat depot is highly innervated by the sympathetic nervous system. With this in mind it is very likely that depot specific sympathetic innervation in humans could be of therapeutic interest in terms of induction of brown fat adipogenesis and early cell fate decisions. This is supported by the findings of Tim Bartness (Georgia State University) using pseudorabies virus tracings (PRV) he has showed that adipose tissue receives depot specific innervation this could also play a role for metabolism in adipocyets (see below).

Adipocyte metabolism

Although control of food intake would seem to be poorly regulated on a day-to-day basis, weight regulation operates with more than 99% precision over the lifetime of most individuals, strongly suggesting a mechanism of fine regulation. One of the most important factors in this mechanism is the adipocyte-secreted hormone leptin. As a general regulator of many physiological systems, leptin plays a part in the treatment of conditions like lipodystrophy and amenorrhea (Jeff Friedman, Rockefeller, USA).

Depot specific regulation of metabolic activity, such as lipolysis results from differences in gene expression. It has been suggested that it could also be maintained by differences in innervation. Using pseudorabies virus (PRV) tracings Tim Bartness (Georgia State University, USA) demonstrated a direct CNS mediated sympathetic innervation of adipose tissue depots. PRV labeled sympathetic outflow neurons extensively co-localize with MC4R mRNA. These findings opens up the distinct possibility that depot specific sympathetic innervation could be an important regulator of adipocyte metabolism and could, to some extent, explain previous findings regarding depot differences in lipolysis. Thus, hypothalamic leptin dependent sympathetic efference could, in a depot specific manner, affect metabolism.

Members of the Foxo family of transcription factors are important regulators of insulin-dependent adipose differentiation. This mechanism contributes to recruitment of new adipocytes in times of plenty (Domenico Accili, Columbia, USA). In an RNAi-based approach Michael Czech (University of Massachusetts, USA) showed that depletion of the transcriptional co-repressor RIP140 and the protein kinase MAP4K4 up-regulates a cluster of genes in the pathway of glucose uptake, including GLUT4. Mechanistically GLUT4 associates with the Akt substrate AS160, a Rab GAP domain containing protein. A crucial step in insulin dependent regulation of GLUT4 docking to the plasma membrane is binding of 14-3-3 proteins to GLUT4 associated AS160. (David James, Garvan Institute, Australia).

Another interesting target for intervention is the retinol binding protein 4 (RBP4) which is secreted from adipocytes and elevated in insulin resistant subjects. Circulating RBP4 is bound to transthyretin. This interaction can be disrupted by the synthetic retinoid fenretinide which leads to the elimination of RBP4 via the kidney. While the exact mechanism of action is under investigation, this treatment nevertheless improves insulin and glucose tolerance (Barbara Kahn, Harvard, USA).

Leslie Kozak (Pennington, USA) discussed the possibility that epigenetic mechanisms acting on adipocyte differentiation could predispose an individual to diet-induced obesity.

Inflammation and adipocyte function

Obesity is associated with chronic low-grade inflammation in adipose tissue. This was first suggested by Hotamisligil and Spiegelman's work demonstrating that fat cells secrete TNF-alpha in the context of obesity. In fact, it now appears that obesity generates conditions that increase the demand on the endoplasmatic reticulum (ER) and trigger the activity of stress and inflammatory signaling pathways including c-Jun N-terminal Kinase (JNK). Based on experiments in which JNK-1 deficiency was shown to reverse ER-stress induced insulin resistance Gökhan Hotamisligil (Harvard, USA) discussed the interesting possibility of using ER/JNK-1 as a target for treatment of insulin resistance and type 2 diabetes.

Similarly, leptin, apart from regulating body weight and reproduction, can also be regarded as a pro-inflammatory cytokine. Leptin stimulates CD4+ Th1 T-helper cells that produce interferon gamma, which might play a role in development of insulin resistance (Graham Lord, Harvard, USA). Bente Klarlund Pedersen (University of Copenhagen, Denmark) showed in a series of human in vivo studies that IL-6 is produced by the contracting muscle and is subsequently released into circulation where it activates lipolysis and fat oxidation. This demonstrates that in addition to being associated with insulin resistance, IL-6 can have beneficial in vivo effects. This suggests that ligands to the IL-6R/gp130beta receptor complex could be interesting as new drug targets.

In spite of immense efforts so far no effective treatment has been made available to help individuals coping with the consequences of living in a "hypercaloric society" where calories are cheap, accessible and sometimes also palatable. A lot of attention has been on central mechanisms that regulate behavior, food intake etc the purpose of this meeting has been to high light peripheral tissue with a clear focus son adipose tissue. It is possible that the interface between central regulation and peripheral response constitutes an accessible way to new drug targets e.g. regulation of adipocyte differentiation. Which could provide a mechanism to dissipate excess calories.

Acknowledgements

We thank participants for comments on our first draft and apologize to those who have been only cursorily or not cited owing to space constraints.

 

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