Hedgehog partial agonism drives warburg-lie metabolism in muscle and brown fat

Diabetes, obesity, and cancer affect upward of 15% of the world’s population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca2+-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of “selective partial agonists,” capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.

Fatty acid metabolism in European sea bass (Dicentrarchus labrax) : effects of n-6 PUFA and MUFA in fish oil replaced diets

Monounsaturated fatty acids (MUFA)-rich and n-6 polyunsaturated fatty acid (n-6 PUFA)-rich vegetable oils are increasingly used as fish oil replacers for aquafeed formulation. The present study investigated the fatty acid metabolism in juvenile European sea bass (Dicentrarchus labrax, 38.4 g) fed diets containing fish oil (FO, as the control treatment) or two different vegetable oils (the MUFA-rich canola/rapeseed oil, CO, and the n-6 PUFA-rich cottonseed oil, CSO) tested individually or as a 50/50 blend (CO/CSO). The whole-body fatty acid balance method was used to deduce the apparent in vivo fatty acid metabolism. No effect on growth performance and feed utilization was recorded. However, it should be noted that the fish meal content of the experimental diets was relatively high, and thus the requirement for n-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA) may have likely been fulfilled even if dietary fish oil was fully replaced by vegetable oils. Overall, relatively little apparent in vivo fatty acid bioconversion was recorded, whilst the apparent in vivo ?-oxidation of dietary fatty acid was largely affected by the dietary lipid source, with higher rate of ?-oxidation for those fatty acids which were provided in dietary surplus. The deposition of 20:5n-3 and 22:6n-3, as % of the dietary intake, was greatest for the fish fed on the CSO diet. It has been shown that European sea bass seems to be able to efficiently use n-6 PUFA for energy substrate, and this may help in minimizing the ?-oxidation of the health benefiting n-3 LC-PUFA and thus increase their deposition into fish tissues.

Free-ranging eastern chipmunks (Tamias striatus) infected with bot fly (Cuterebra emasculator) larvae have higher resting but lower maximum metabolism

Given the ubiquity and evolutionary importance of parasites, their effect on the energy budget of mammals remains surprisingly unclear. The eastern chipmunk (Tamias striatus (L., 1758)) is a burrowing rodent that is commonly infected by cuterebrid bot fly (Cuterebra emasculator Fitch, 1856) larvae. We measured resting metabolic rate (RMR) and cold-induced [Vo.sub.2]-max (under heliox atmosphere) in 20 free-ranging individuals, of which 4 individuals were infected by one or two larva. We found that RMR was significantly higher in chipmunks infected by bot fly larvae (mean [+ or -] SE = 0.88 [+ or -] 0.05 W) than in uninfected individuals (0.74 [+ or -] 0.02 W). In contrast, V[O.sub.2]-max was significantly lower in chipmunks infected by bot fly larvae (4.96 [+ or -] 0.70 W) than in uninfected individuals (6.37 [+ or -] 0.16 W). Consequently, the aerobic scope (ratio of [Vo.sub.2]-max to RMR) was negatively correlated with the number of bot fly larvae (infected individuals = 5.74 [+ or -] 1.03 W; noninfected individuals = 8.67 [+ or -] 0.26 W). Finally, after accounting for the effects of body mass and bot fly parasitism on RMR and [Vo.sub.2]-max, there was no correlation between the two variables among individuals within our population. In addition to providing the first estimate of [Vo.sub.2]-max in T. striatus, these results offer additional evidence that bot fly parasitism has significant impacts on the metabolic ecology of this host species.

Energy metabolism and animal personality

In this paper we show how animal personality could explain some of the large inter-individual variation in resting metabolic rate (MR) and explore methodological and functional linkages between personality and energetics. Personality will introduce variability in resting MR measures because individuals consistently differ in their stress response, exploration or activity levels, all of which influence MR measurements made with respirometry and the doubly-labelled water technique. Physiologists try to exclude these behavioural influences from resting MR measurements, but animal personality research indicates that these attempts are unlikely to be successful. For example, because reactive animals “freeze” when submitted to a stress, their MR could be classified as “resting” because of immobility when in fact they are highly stressed with an elevated MR. More importantly, recent research demonstrating that behavioural responses to novel and highly artificial stimuli are correlated with both behaviour and fitness under more natural circumstances calls into question the wisdom of excluding these behavioural influences on MR measurements. The reason that intra-specific variation in resting MR are so weakly correlated with daily energy expenditure (DEE) and fitness, may be that the latter two measures fully incorporate personality while the former partially excludes its influence. Because activity, exploration, boldness and aggressiveness are energetically costly, personality and metabolism should be correlated and physiological constraints may underlie behavioural syndromes. We show how physiological ecologists can better examine behavioural linkages between personality and metabolism, as required to better understand the physiological correlates of personality and the evolutionary consequences of metabolic variability.

Skeletal muscle nitric oxide signalling and exercise: a focus on glucose metabolism

Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components.

A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance.

This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise.