Adipose tissue mitochondrial respiration: Key insights from RYGB-induced weight loss.

Abstract

It has become increasingly well accepted that adipose tissue mitochondria are important regulators of whole body glucose and lipid metabolism (1). Reductions in adipose tissue mitochondrial proteins occur early during the pathogenesis of insulin resistance (2), while adipose mitochondrial content is increased following treatment with the insulin-sensitizing compounds thiazolidinediones (3). In this issue of Obesity, Hansen et al. (4) provide intriguing insight into the regulation of mitochondrial content and function in adipose tissue samples from obese subjects with or without type 2 diabetes following Roux-en-Y gastric bypass surgery (RYGB). A key take-home message of this study is the importance of identifying the proper means with which to normalize adipose tissue respiration data. In both groups of subjects, adipose tissue respiration was increased following RYGB-induced weight loss when expressed relative to tissue weight. However, an important point is that RYGB leads to massive weight loss (>30 kg) and decreases in adipocyte size due to reductions in lipid content. Consequently, for a given amount of tissue analyzed, there are a greater number of cells, and thus mitochondria, per unit tissue. When normalizing to either cell, or mitochondrial number, the weight loss-induced increases in adipose tissue respiration were lost. These findings clearly highlight the need for careful consideration when analyzing adipose tissue respiration, as the choice of denominator can greatly influence the interpretation of the data. A second important finding of this article is that increases in adipose tissue mitochondrial content do not appear to be required for the RYGB-mediated improvements in glucose homeostasis. In this regard, mitochondrial density was not increased with weight loss despite robust increases in systemic insulin sensitivity. However, there were slight but significant increases in the ratio between maximally coupled and uncoupled respiration, i.e., the phosphorylation system control ratio (P/E ratio), suggesting improvements in mitochondrial function following weight loss. It should be stressed, however, that it is not evident from the current data set how quickly the increase in the P/E ratio occurs as this data was only reported from respiration experiments at the inclusion of the study and 18 months following RYGB. Thus, it is not clear whether the improvement in mitochondrial function in adipose tissue is a cause or a consequence of improvements in insulin sensitivity. This is a particularly important point to consider as previous work has demonstrated a role for insulin in the regulation of skeletal muscle mitochondrial function (5). The current investigation is unique in that it examines, longitudinally, changes in adipose tissue respiration and mitochondrial density following RYGB. With this being said, the conclusions that can be drawn regarding the role of adipose tissue mitochondria in RYGB-mediated improvements in insulin sensitivity are limited as only subcutaneous adipose tissue was examined. While procuring visceral adipose tissue samples in a pre–post intervention design would be difficult to execute, these studies would prove to be beneficial in confirming the association of alterations in adipose tissue mitochondrial content and/or function in a more metabolically active fat depot to changes in whole body glucose metabolism.