Enhancing the Metabolic Benefits of Bariatric Surgery: Tipping the Scales With Exercise Open Access

The Roux-en-Y gastric bypass (RYGB) procedure is regarded as the gold-standard metabolic surgery in the U.S., rivaling sleeve gastrectomy as the most common bariatric surgery procedure. In addition to considerable weight loss, patients undergoing RYGB exhibit remarkable improvements in multiple metabolic abnormalities, including remission of type 2 diabetes and improvements in insulin sensitivity (1–3). These adaptations can be divided into those that prevail acutely in response to severe energy restriction (e.g., improved glycemia, improved hepatic insulin sensitivity) versus those that occur with more latency, associated with weight loss (e.g., improved peripheral insulin sensitivity) (2,4). In many cases, the long-term improvements in peripheral insulin sensitivity align with the degree of weight lost in the months following the RYGB procedure (5,6). Although the point has been made that peripheral insulin sensitivity remains well below what is observed in lean healthy control subjects in spite of substantial weight loss following RYGB, there is hearty evidence that, if anything, the improvements in peripheral insulin sensitivity following RYGB are greater than would be predicted based on weight loss alone (2,7). For example, Camastra et al. (2) followed morbidly obese RYGB patients with or without diabetes up to 1 year following the procedure, evaluating peripheral insulin sensitivity using the euglycemic-hyperinsulinemic clamp procedure. While it is true that insulin-stimulated glucose disposal 1 year following RYGB (38.5 μmol/min/kg fat-free mass [FFM]) remained well below values measured in lean control subjects (64.0 μmol/min/kg FFM), the values were higher than obese control subjects (29.7 μmol/min/kg FFM) who had BMIs that were similar to RYGB patients 1 year following surgery. Nevertheless, there is tremendous interest and opportunity for therapeutic strategies to enhance the metabolic improvements as parallel therapy in the months or years following RYGB.

One such therapeutic strategy is exercise, which has pleiotropic benefits to many tissues, particularly insulin-sensitive tissues such as the skeletal muscle (8), liver (9), and adipose tissue (10). Given that exercise improves whole-body insulin sensitivity and glycemic control in type 2 diabetes (11,12), it is logical that exercise following bariatric surgery may confer additional improvements in cardiometabolic risk factors beyond what would be observed following surgery alone. Indeed, this was shown to be the case in a recent randomized controlled trial that was designed to evaluate the impact of a 6-month exercise intervention on cardiometabolic risk factors following RYGB surgery (13). This study found that 120 min of exercise per week improved insulin sensitivity by 30% compared with post-RYGB patients who were sedentary. Exercise also improved glucose effectiveness (i.e., the ability of glucose to suppress endogenous glucose production and stimulate glucose uptake). This study clearly showed that exercise at a realistic, achievable volume and intensity in the months following RYGB surgery has the potential to substantially improve physical fitness and cardiometabolic risk beyond what surgery alone can do. It is important to note that exercise did not change body weight, fat mass, or fat distribution compared with the sedentary group, meaning that the improvements in insulin sensitivity with exercise cannot be explained on the basis of additional reductions in adiposity.

In this issue of Diabetes, Coen et al. (14) provide some new mechanistic insights into how exercise may improve insulin sensitivity in the post-RYGB period. A main focus of inquiry was on skeletal muscle mitochondria because these organelles have been linked to insulin resistance through their role in fatty acid oxidation (15) and oxidative stress (16). In the presence of so-called mitochondrial dysfunction or when lipid supply simply outpaces oxidation, there is an accumulation of bioactive intramyocellular lipid metabolites (sphingolipids, diacylglycerols) that are known to interfere with insulin signaling (17,18). As exercise stimulates mitochondrial biogenesis and reduces intramyocellular diacylglycerols and ceramides, it is reasonable to expect that this may be the mechanism by which exercise enhances the improvements in insulin sensitivity in the months following RYGB. In a subset of 101 individuals from the larger trial described above (13), the investigators comprehensively evaluated mitochondrial physiology and measured the abundance of lipid metabolites (sphingolipids, diacylglycerols) in the skeletal muscle. The main important findings of this study were that the additional improvements in insulin sensitivity with post-RYGB exercise training were accompanied by increased mitochondrial capacity for oxidizing both carbohydrate and lipid substrates (state 3 respiration) in the absence of any evidence for expanded mitochondrial mass. As a side note of interest, RYGB without exercise did not improve mitochondrial oxidative capacity, but there was some evidence of mitochondrial remodeling that was associated with increased phosphorylation capacity in the absence of any increase in the overall capacity of the electron transport system or mitochondrial abundance. This finding is of great interest given the current ambiguity in the literature about the effects of caloric restriction on skeletal muscle mitochondrial physiology. Perhaps as a consequence of increased mitochondrial lipid oxidation, exercise also decreased total sphingolipids and total ceramide levels in the skeletal muscle, providing an attractive mechanistic link to improved insulin sensitivity. Interestingly, muscle diacylglycerols remained unchanged following RYGB with or without exercise and were dissociated from changes in insulin sensitivity. The role of diacylglycerols as mediators of insulin resistance in the skeletal muscle continues to be murky.

Coen et al. (14) provide compelling links between muscle mitochondrial function, sphingolipids, and the improvements in insulin sensitivity with exercise following RYGB (Fig. 1). A noteworthy feature of this study is that the investigators used rigorous gold-standard methods to carefully evaluate their main outcomes. Mitochondrial function was evaluated using high-resolution respirometry, enzyme assays, protein expression, and cardiolipin levels. Mass spectrometry was used to quantify the distinct molecular species of sphingolipids and cardiolipin, which offered a better window into underlying physiology than simply measuring the total levels of these lipids. Furthermore, the robust sample size of more than 100 patients is uncommon in painstakingly controlled mechanistic studies in humans. As expected, the study leaves some lingering questions. Why did obese RYGB patients fail to exhibit the classic increase in mitochondrial abundance that is well documented with exercise? It is possible that these individuals exhibit some degree of exercise resistance that others have described in people with insulin resistance and type 2 diabetes (19,20). It is also possible that there are competing signals from exercise and caloric restriction whereby exercise stimulates mitochondrial biogenesis while caloric restriction decreases mitochondrial biogenesis (21). The improvement in mitochondrial capacity in the absence of mitochondrial biogenesis is at first puzzling but may be explained by the improved quality of mitochondrial proteins. Although mitochondrial-derived reactive oxygen species were not measured, the increased levels of tetralinoleoyl cardiolipin suggest lower levels of oxidative stress in the group that performed exercise. Regardless of the underlying mechanisms, it is clear that exercise is an important adjunctive therapy in bariatric surgery patients and may help balance the benefits and risks of RYGB that have been recently highlighted (22).