Stewing in Not-So-Good Juices: Interactions of Skeletal Muscle With Adipose Secretions.

Derangements in both skeletal muscle and adipose tissue are clearly linked with obesity, type 2 diabetes, and insulin resistance. The complex mechanistic interactions between muscle and adipose tissue are, however, only recently beginning to be more fully understood in the pathogenesis of these epidemic metabolic diseases. White adipocytes are not homogenous but rather vary considerably in their metabolic and inflammatory profile, defined in part by adipose depot differences. For example, visceral adipocytes differ from subcutaneous adipocytes in their sensitivity to lipolytic stimuli and inflammatory and cytokine profiles (1). Yet, it has remained unclear how secreted factors from different types of adipocytes may uniquely impact skeletal muscle metabolism, and somewhat removed in primacy of contemporary interest, whether these affect muscle structure and contractile function. In this issue of Diabetes, Pellegrinelli et al. (2) use elegant three-dimensional human primary cell culture experiments to examine the effects of secreted factors from both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) on myocyte structure and the atrophy program within muscle. The secretory profile from adipocytes isolated from VAT was different from those isolated from SAT in lean subjects, while SAT from obese subjects manifested an intermediate pattern that was not as pronounced as VAT in negative repercussions. Myocytes cocultured with VAT were smaller, a morphology that seems consistent with a gene and protein expression profile indicative of, and predisposing to, muscle atrophy. Striking among this pattern was the suppression of key components of muscle contractile elements, notably troponin and other constituents comprising the sarcomere. Together with these, there was a repression of pathways of oxidative metabolism and protein synthesis. The authors conclude that VAT adipocytes create an environment in which the inflammatory cytokines interleukin (IL)-6 and IL-1b, which are deleterious to muscle, are prominent (Fig. 1). This study advances our understanding in many important ways of the type of interactions between muscle and fat. The use of innovative three-dimensional cocultures using human cells provides an important methodological precedence and a framework for future studies in this area. This model system likely provides a more physiological context to examine both the release and impact of secreted factors in governing cell-to-cell interactions. The use of human primary cells—and adipocyte cultures from different regional adipose tissue depots— offers promise for more immediacy in translation to human biology than afforded from single tissue primary cultures; yet, one cannot imagine that a binary culture fully recapitulates in vivo physiology. Even so, it can be hoped that this type of platform will enable more fidelity in identifying novel targets for intervention. Despite the important insights into the interaction between VAT and muscle that were achieved in this investigation, this study was limited in that muscle cell function was not actually measured. Thus, we cannot interpret the findings to firmly conclude that VAT or factors secreted from VAT directly affected muscle cell contractility function. Older obese humans have larger muscles (3) but reduced muscle strength and quality (strength per unit mass). Thus, there must be other factors at play in vivo (e.g., mechanical load, anabolic milieu, and others) that are important yet not adequately assessed ex vivo in cell culture systems. An area that we believe warrants additional consideration concerns increased expression of extracellular matrix in insulinresistant skeletal muscle (4,5). It would have been of great interest in the studies by Pellegrinelli et al. (2) to have learned whether, in association with the effect of the