Focus issue: the signaling skinny on obesity.

Abstract

The enormous literature and ever-growing media coverage on obesity attest to our concern about being overweight. Overeating has become a chronic, deadly, worldwide epidemic. Examination of our super-sized society from medical, genetic, evolutionary, social, and economic perspectives reflects both our need to understand why we overconsume and our desire to stop getting fat. This week's special issue of Science examines recent discussions and debates concerning environmental influences on obesity, the science of hunger and satiety signals, and the translation of basic science into clinical solutions. Recent molecular insights into the signaling processes that affect obesity, as well as the diseases that result from obesity, are also highlighted in this week's STKE Focus Issue. Both biology and environment contribute to obesity. As Hill et al ., Friedman, and Pi-Sunyar all point out in Science's special issue, the obesity we face today is the result of a history of abundant and cheap food and a sedentary life-style. Put more scientifically, the energy balance equation has been tipped--calorie intake grossly outweighs calorie expenditure. It is widely agreed that behavioral change to reverse this situation is essential. As Pi-Sunyar points out, improved education is part of the long-term solution. In the meantime, Hill et al . suggest a short-term strategy by assigning real numbers to the energy balance equation. Further solutions await the identification of the molecules and biological networks that regulate energy balance. For example, a number of hormonal factors, such as leptin, appear to control food intake, although, as Trayhurn describes in an STKE Perspective, the nature of the link between leptin and obesity is debatable and leptin is likely a multiple action hormone. On the other hand, catecholamines, acting through β-adrenergic receptors, regulate energy expenditure (see Connections Map of the adrenergic signaling pathway). Cytokines such as tumor necrosis factor (TNF) have also been implicated in weight control. For example, increased TNF levels have been asssociated with chronic weight loss that reflects a condition of extreme energy expenditure and depletion of body mass, as described by Tracey in a Perspective from the STKE Archive (also see Connections Map of the TNF signaling pathway). So a molecular framework of the molecules and signaling pathways that regulate energy balance is emerging, and the impact of the environment on this robust but plastic system is becoming apparent. A war is being waged not only on obesity, but on the plethora of chronic diseases linked to obesity, including type II diabetes, chronic heart disease, tissue degeneration, and possibly cancer. The clinical battle against diabetes has included the development of drugs that target the nuclear receptor called the gamma subtype of the peroxisome proliferator-activated receptor (PPARγ). Not only does this receptor promote adipogenesis, but it also enhances insulin sensitivity. Attenuated insulin action results in decreased glucose uptake, a hallmark of type II diabetes. In an STKE Perspective from the archives, Rangwala and Lazar describe recent efforts to generate selective PPARγ modulators (SPPARMs), agonists that have insulin-sensitizing activities without affecting fat cell formation. PPARγ also regulates the expression of genes that control glucose metabolism, such as the insulin-sensitive glucose transporter Glut4 found in adipose and skeletal muscle tissue. The STKE Perspective by Kandror discusses controversies about mechanisms of regulating Glut4 and how Glut4 is translocated from intracellular vesicles to the cell surface to control glucose uptake. A major problem in our ability to determine the relationship between Glut4 insertion and glucose uptake seems to lie in techniques used to measure Glut4 translocation. An STKE protocol by Tengholm et al . describes a new microscopic technique to visualize Glut4 insertion into the plasma membrane in adipocytes, as well as the simultaneous insulin-dependent activation of phosphatidylinositol 3-kinase (PI3K), and provides another means to assess whether a correlation indeed exists between Glut4 insertion and PI3K activation. Insulin, of course, is one of the key hormones controlling the cellular uptake of sugar from the bloodstream and a regulator of cellular metabolism (see the Connections Map of the insulin signaling pathway by White). In addition to enforcing a healthy life-style solution (prevention), the obesity crisis demands a focus on better treatments. As Friedman points out, much progress is needed in understanding how the brain processes diverse information such as hunger and satiety signals, sensory input, and emotional states. And as Pi-Sunyar states, obesity has biological associations that have yet to be explored, such as its relationship with the immune system. For instance, Krebs and Hilton describe how signaling components once thought to be exclusive to cytokine signaling pathways regulate insulin signaling. We remain hungry for the answers to our fast-food dilemma. Featured in this Focus Issue Related Resources at STKE