The ninth Colloque Médecine et Recherche of la Fondation Ipsen devoted to Endocrinology, held in Paris on December 4, 2009, has reviewed the recent progress in understanding the regulation of fat storage in the body and the consequences of the breakdown of this regulation.
Among these breakdowns of regulation are insulin resistance leading to type-2 diabetes; cardio-vascular disease and stroke, kidney failure and cancer. The meeting has been organised by Karine Clément (Institut des Cordeliers, Paris, France), Bruce Spiegelman (Harvard Medical School, Boston, USA) and Yves Christen (la Fondation Ipsen, Paris, France) and thirteen leading scientists have presented their latest research
The many forms of adipocyte regulation that were discussed at this meeting hold out promise for developing therapeutic interventions, some sooner than others. All the speakers discussed the potential applications of their work and the questions that need answering to make such interventions a reality.
Fatty tissue, distributed throughout the body, was for many years considered as a passive store for fat. This perception began to change with the discovery in 1994 that fat cells, or adipocytes, secrete a hormone, leptin, which is involved in the control of food intake and a variety of other regulatory functions throughout the body. Now the white adipose tissue (WAT), the main fat-storing tissue, is recognized as a complex organ making a crucial contribution to the control of food intake, energy balance, glucose and lipid metabolism, immunity and reproduction (Philipp Scherer, University of Texas Southwestern Medical Center, Dallas, USA). As well as mature adipocytes, the WAT contains adipocyte progenitor cells, macrophages, blood vessels, and other regulatory and protective components (Karine Clément, Institut des Cordeliers, Paris, France).
Fat is stored as triglycerides in the adipocytes when energy input to the body exceeds energy output. When energy demands are high, it is mobilized by lipolysis and details of the lipolysis pathways, which break the triglycerides down into fatty acids and glycerol, are now being elucidated (Dominique Langin, Inserm U858, Université Paul Sabatier, CHU Toulouse, Toulouse, France). More frequently, the imbalance between energy input and output persists, so that over many years the person becomes first over-weight and then obese. As this happens, the functions of the WAT become profoundly altered, with reduced capacity for fat storage; more macrophages and increased inflammation; oxidative stress; and hypoxia (Karine Clément, Institut des Cordeliers, Paris, France; Scherer, University of Texas Southwestern Medical Center, Dallas, USA). Consequences of this are the spread of inflammation to other organs and fat being stored in liver and muscles, as well as the development of insulin resistance, leading to type-2 diabetes (Karine Clément, Institut des Cordeliers, Paris, France; David Savage, University of Cambridge, Cambridge, UK).
The inflammation in the WAT seems to result from the poor oxygenation of the expanded tissue, which stimulates the production of pro-inflammatory signalling molecules and switches the adipocytes to producing lactate (Paul Trayhurn, University of Liverpool, Liverpool, and University of Buckingham, Buckingham, UK). The adipocytes secrete a hypoxia-induced factor that promotes the production of collagen fibres, making the fat body more rigid and limiting its ability to store fat (Philipp Scherer, University of Texas Southwestern Medical Center, Dallas, USA). In the stressed adipocytes, the activity of genes associated with metabolic pathways decreases and gene activity associated with inflammatory pathways in the macrophages in the WAT increases (Dominique Langin, Inserm U858, Université Paul Sabatier, CHU Toulouse, Toulouse, France).
A further complication to the understanding of WAT functions is that the fat deposits in the different areas of the body do not all function in the same way. Furthermore embryological studies have now demonstrated that the adipocytes in different regions of the body have different embryonic origins (Christian Dani, Université de Nice Sophia-Antipolis, Nice, France). In adults, contrary to previous understanding, adipocytes do die and they are replaced at a rate of about 10% per year (Peter Arner, Karolinska Institute, Huddinge, Sweden). A pool of adipocyte progenitor cells in adults provides for replacement of outworn cells and allows the WAT to expand as the demand for fat storage increases (Christian Dani, Université de Nice Sophia-Antipolis, Nice, France). When weight is lost, fat is lost from the adipocytes but the number of cells remains steady. The turnover rate is set in adolescence, is higher in obese than in lean subjects and is linked to susceptibility to develop insulin resistance and type-2 diabetes (Peter Arner, Karolinska Institute, Huddinge, Sweden).
Macrophages resident in the WAT secrete factors that stimulate the adipocyte progenitors to produce activin A, a molecule that promotes their proliferation (Christian Dani, Université de Nice Sophia-Antipolis, Nice, France) – another example of the tight regulatory communication between adipocytes and macrophages that changes balance as stored fat increases. Key pathways in the switch between proliferation of adipocyte progenitors and their differentiation into adult adipocytes are being revealed using a whole genome approach (Evan Rosen, Beth Israel Deaconess Medical Center, Boston, USA).
One obvious way to restore the energy input – output balance, though one that is often difficult to implement, is to increase energy output. Consequently, there is much excitement about the recent discovery that some human adults have another type of fat, the brown adipose tissue (BAT), which is dedicated to the generation of heat (Sven Enerbäck, University of Gothenburg, Göteborg, Sweden). Previously known only in rodents, animals that hibernate and human infants, brown fat cells rapidly take up triglycerides and, through a unique mitochondrial mechanism, convert them to heat rather than the normal synthesis of the energy-rich molecule ATP. Studies on mice are revealing that BAT protects against obesity, insulin resistance and type-2 diabetes (Sven Enerbäck, University of Gothenburg, Göteborg, Sweden; Barbara Cannon, Stockholm University, Stockholm, Sweden).
A further discovery makes the presence of brown fat not just lucky for those adults who have it: under certain laboratory conditions, white fat cells can be converted to brown. As the therapeutic implications of this potential are clear, the molecular mechanisms and the requisite conditions that promote this conversion are now under intense investigation (Dominique Langin, Inserm U858, Université Paul Sabatier, CHU Toulouse, Toulouse, France; Christian Dani, Université de Nice Sophia-Antipolis, Nice, France; Bruce Spiegelman, Harvard Medical School, Boston, USA; Stephen Farmer, Boston University School of Medicine, Boston, USA).
Regulation of body weight concerns not only the WAT: the brain is also involved. This level of regulation turns out to be quite subtle, with the hypothalamic and higher brain circuits protecting more against weight loss than against weight gain (Rudolph Leibel, Columbia University, New York, USA). As well as making evolutionary sense, here is a mechanism that supports common experience that it is far easier to gain weight than to lose it! Understanding this complex neural and hormonal regulation may well point to ways to shift the balance towards weight loss. Genetics of course also plays a part and studies of single-gene mutations that affect the functioning of the WAT are helping to dissect the molecular pathways underlying insulin resistance (David Savage, University of Cambridge, Cambridge, UK).