Partial White Adipose Tissue Lipolysis Inhibition: A Novel Approach to Improve Insulin Sensitivity?
Circulating fatty acids (FAs) have an unclear relationship to insulin sensitivity. During fasting and exercise, FAs from white adipose tissue (WAT) lipolysis are delivered to peripheral tissue to meet energy needs. In obesity, excess circulating FAs are thought to drive the development of insulin resistance. Girousse et al., through a variety of in vivo and in vitro human and mouse studies, probe this relationship between WAT lipolysis to insulin sensitivity. First, using human WAT explants from subjects with a large range of BMIs and also pre- and post-bariatric surgery subjects, decreasing WAT lipolysis rate was associated with improving insulin sensitivity. Next, the authors identified a mouse model (haploinsufficient hormone-sensitive lipase [HSL+/-] mice) with reduced lipolysis rates and unchanged fat mass to explore this relationship. Using this model, HSL+/- mice were found to have unaltered FA levels, but did have diminished FA uptake and storage in peripheral tissue. Importantly, HSL+/- mice had improved insulin tolerance and glucose metabolism during high-fat diets, where WAT, skeletal muscle, and liver in the HSL+/- mice each had evidence of improved insulin/glucose tolerance. Probing this question by a different approach, high-fat diet–fed mice were treated for 7 days with an HSL inhibitor, resulting in improved insulin tolerance without a change in fat mass. Confirming these findings in a human model, studies using human adipocytes with HSL knockdown had decreased FA oxidation rates in conjunction with elevated insulin–stimulated glucose uptake. Taken together, these compelling data raise the question of whether partial inhibition of WAT lipolysis can be a strategy to improve insulin sensitivity. — Brian T. Layden, MD, PhD
Girousse et al. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS Biol 2013;11:e1001485
A Tiny Fish Gets Big on Drug Discovery
Obesity and diabetes and the risk they confer for cardiovascular disease, renal failure, neurological complications, and mortality are the most important public health issues in the U.S. and developed countries. Therefore, there is a clear need to develop new drugs and therapeutic strategies to prevent or even cure these disorders. Increased gluconeogenesis has been shown to occur in type 2 diabetes, and drugs targeting this process are likely to impact glycemic control in diabetic individuals. Classic, standard drug discovery is performed using automated high-throughput screening of thousands of compounds on cell culture systems. However, the complexity of metabolic disorders is impossible to recapitulate in cell culture. Over the past few years, whole-organism screening of zebra fish has emerged as a new platform that integrates the power of analysis of high throughput screening of cell-based methods with the advantage of the whole animal physiological integration. New data from Gut et al. has adapted the zebra fish larvae screening method to test the effect of 2,400 bioactive compounds on whole-body energy metabolism. Using a reporter gene approach, the investigators monitored gluconeogenesis in the liver and pronephros of living animals and preselected 60 compounds. Among these drugs, some were already well-known regulators of glucoses homeostasis, but two new agents, PK 11195 and Ro5-4864, were identified as capable of activating the expression of the reporter gene pck1 and reducing glucose without any toxicity. Most importantly, PK 11195 was shown to reduce weight gain as well as fasting blood glucose and to improve glucose tolerance in a mouse model of obesity and diabetes. These new data provide novel avenues for drug discovery and the identification of molecular mechanisms that are therapeutically relevant for the treatment of obesity and diabetes. — Nathalie Fiaschi-Taesch, PhD
Gut et al. Whole-organism screening for gluconeogenesis identifies activators of fasting metabolism. Nat Chem Biol 2013;9:97–104
The Circadian Rhythm of Insulin Action: Lessons Learned From Clockless Mice
Circadian rhythms occur in almost all species and control vital aspects of physiology—from sleep and arousal to feeding and metabolism. Cross-talk between metabolic and circadian systems allows organisms to anticipate physiological needs relevant to the daily light/dark cycle and to adapt the phase of internal cycles to changes in the environment. It is not surprising that disruption of the circadian cycle has been associated with metabolic impairment, increased risk of obesity, type 2 diabetes, and cardiovascular disease. A new study by Shi et al. provides some interesting possibilities as to how these connections might be mediated. The investigators examined the circadian rhythm of insulin action in wild-type (WT) mice and mice in which the key circadian clock gene Bmal1 was knocked out. Mutant mice had a severely disrupted or obliterated circadian system. They found that WT mice were most resistant to insulin during the inactive portion of the daily cycle. The clock-interrupted Bmal1-knockout mice were relatively insensitive to insulin, and rather than showing normal diurnal variation, they were "locked" into the trough of insulin action and lacked rhythmicity in both insulin action and activity patterns. When rhythmicity was restored in the knockout mice by transgenic expression of the Bmal2 paralog, Bmal2, insulin action, fasting glucose levels, Akt signaling, fat accumulation, and activity patterns were all restored to normal. In response to a high-fat diet, both Bmal1-knockout mice and WT mice made arrhythmic by exposure to constant light were more prone to become obese. This may be partly due to adipocyte function and its rhythmicity. Adipose tissue explants obtained from high-fat diet–fed WT mice had a longer periodicity than animals on a chow diet. Collectively, these data demonstrate that disturbing the natural rhythmicity of insulin action disrupts the internal environment of insulin-sensitive tissue, thereby predisposing the animals to insulin resistance and obesity. These findings highlight the importance of considering timing/circadian phase in experimental design and in data interpretation. Moreover, the results provide insight into the negative metabolic consequences observed in humans whose circadian clocks are disturbed. — Jenny Tong, MD, MPH
Shi et al. Circadian disruption leads to insulin resistance and obesity. Curr Biol 2013;23:372–381
Serotonin Released From Gut: A Novel Counter-Regulatory Hormone
Multiple counter-regulatory systems have evolved to ensure glucose supply during fasting. The role of the gut in the regulation of glycemic status has not been well explored beyond its key role in the absorption of nutrients. A new study suggests that gut-derived serotonin functions as a novel regulatory system to maintain blood glucose in fasting conditions. Both tryptophan hydroxylase 1 (Tph1; an enzyme responsible for serotonin synthesis in peripheral organs) and serotonin itself in the gut increased in response to fasting, suggesting a functional relevance of gut serotonin in the fasted state. Pharmacological serotonin increased plasma concentrations of glycerol and free fatty acids in both fed and fasted conditions in a dose-dependent manner, which was mediated through direct action on adipose tissues. Further, in the presence of gluconeogenic substrates, serotonin increased plasma glucose concentrations, caused glucose intolerance, and increased glucose output from primary hetapocytes through activating key gluconeogenic enzymes, suggesting that gut-derived serotonin can mobilize fat utilization and increase glucose output from the liver. Gut-specific elimination of serotonin synthesis by deletion of Tph1 reduced hepatic glucose production and improved glucose tolerance. These were reversed by serotonin, confirming an importance of gut-derived serotonin in glucose homeostasis. Adipose tissue–specific deletion of Htr2b, one of many serotonin receptors, led to blunted response in both fasting- and serotonin-induced lipid mobilization; this was associated with reduced phosphorylation and activity of hormone-sensitive lipase, demonstrating a role of serotonin action through Htr2b in adipose tissues by mobilizing lipid utilization in response to fasting. These data suggest that gut-derived serotonin is a novel counter-regulatory hormone that promotes glucose production through coordinated action on adipose and liver tissues. Pathophysiologically, uncontrolled hepatic glucose production can lead to glucose intolerance and type 2 diabetes. Inhibition of peripheral serotonin synthesis greatly reduced hepatic glucose production and improved glucose homeostasis in mice fed high-fat diets, demonstrating the potential utility of inhibition of peripheral serotonin action in reversing two important consequences of insulin resistance and type 2 diabetes, namely increased hepatic glucose production and increased adipose tissue lipolysis. The importance of these findings in human physiology and pathology remains to be explored. — Qingchun Tong, PhD
Sumara et al. Gut-derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab 2012;16:588–600
