METABOLISM. Food alert. Joshua P. Thaler and David E. Cummings. The gut
prevents nutrient .... nisms are quickly inactivated by the ingestion of a fat-rich diet
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Vol 452|24 April 2008
NEWS & VIEWS METABOLISM
Food alert Joshua P. Thaler and David E. Cummings
The gut prevents nutrient overload during a meal by promoting satiety and enhancing insulin secretion. New findings show that nutrients in the gut also activate a neural circuit that increases insulin sensitivity.
LCFA-CoA
– Hindbrain
Afferent vagal nerve
Food
Efferent vagal nerve
Eating is essential to life, yet its episodic nature necessitates physiological adaptations to avoid excesses or deficits in circulating fuels, especially glucose and lipids1. As the first point of contact with ingested food, the gastrointestinal tract is ideally positioned to initiate after-meal adaptations. Indeed, when nutrients are delivered into the gut, homeostatic mechanisms in place there are activated so that blood glucose levels are perturbed less than when nutrients are delivered directly into the blood. An established reason for this effect is that ingested nutrients stimulate the release of gut peptides called incretins, which enhance secretion of the hormone insulin, the main controller of blood glucose levels2. On page 1012 of this issue, Wang et al.3 describe another gut-mediated mechanism that contributes to the regulation of glucose levels: a neural circuit, initiated in the intestine in response to nutrient sensing, that increases sensitivity to insulin. Among the main products of dietary-fat digestion are long-chain fatty acids (LCFAs), which are cleaved from triglycerides by gastrointestinal enzymes. To investigate the effect of intestinal LCFAs on glucose homeostasis in rats, Wang and colleagues used the sophisticated method of pancreatic clamping, which allows the insulin sensitivity of specific tissues to be quantified. They found that infusion of calorically insignificant amounts of triglycerides directly into the animals’ duodenum (the upper portion of the small intestine) markedly and rapidly increased insulin sensitivity. Insulin not only promotes glucose uptake into tissues but also suppresses production by the liver of glucose derived from stored fuels; both actions lower blood sugar levels. Intestinal lipid infusions in Wang and colleagues’ experiments specifically increased insulin sensitivity of the liver, reducing glucose output from this organ without affecting tissue glucose uptake. In unclamped rats, duodenal lipid infusions also contributed to glucose homeostasis, establishing the relevance of this mechanism to normal physiology. How can lipids in the intestine trigger these systemic effects? The authors found that, initially, an LCFA metabolite called LCFA-CoA is sensed by the intestine. (The exact location
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Liver
CCK Internal fuels
LCFA-CoA Lipids Incretins Insulin Pancreas
Intestine
Muscle
Blood glucose
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Figure 1 | The intestine’s contributions to glucose homeostasis. Blood glucose comes from two sources: externally from ingested food, and internally from the mobilization of stored fuels by the liver. Following a meal, lipid sensing in the intestine initiates processes that limit both of these sources through several mechanisms. For example, the intestine secretes satiation peptides such as cholecystokinin (CCK) that promote meal termination, reducing further food intake (red pathways). Intestinal incretin peptides augment insulin secretion and also reduce food intake (green pathways). Wang et al.3 now demonstrate that LCFA-CoA molecules in the intestine activate an intestine–brain–liver neural circuit that enhances insulin sensitivity, suppressing glucose output by the liver (purple pathways). In the brain, LCFA-CoA signalling also decreases both production of glucose by the liver and food intake. Thick red bars depict inhibition. 941
NEWS & VIEWS
and identity of the intestinal sensor cells are unknown.) They also showed that the link between lipid sensing in the gut and insulin action in the liver involves an intestine–brain– liver circuit within the parasympathetic nervous system, a subdivision of the peripheral nervous system. The LCFA-CoA signal passes from the gut, along the vagus nerve to the brain, through the hindbrain, and then back down vagal nerve branches that terminate in the liver (Fig. 1). Wang and colleagues did not elucidate the details of communication between intestine and vagus, so intermediary roles for gut hormones, including incretins, remain possible. They found that disruption of any component of this neural circuit eliminated the insulin-sensitizing effect of intestinal lipids, without affecting baseline glucose homeostasis. So the intestine–brain–liver axis serves not as a basal regulator of insulin sensitivity but as a first responder to meals, preventing the circulating nutrient excess that would occur with profligate mobilization of internal fuel stores following a meal. Together with previous work, these findings3 portray the gut as a rapid-response coordinator of energy input, influencing both the size of meals and the metabolic fate of the ingested nutrients. In response to food, the intestine produces satiety factors that promote meal termination4. The archetype, cholecystokinin, the production of which is stimulated by intestinal LCFAs, reduces food intake via an intestine– vagus–hindbrain pathway (Fig. 1). Furthermore, food consumption stimulates gut incretins to enhance insulin secretion. Lastly, Wang et al. show that LCFA sensing in the intestine also increases insulin sensitivity in the liver, minimizing inappropriate nutrient efflux from this organ after meals. So, more than just a calorie conduit, the intestine emerges as a neuroendocrine organ that regulates food intake as well as insulin secretion and action to improve glucose tolerance and to promote a seamless after-meal transition from fuel breakdown to storage. Wang and colleagues’ observations complement previous studies of LCFA signalling in the brain. As they do in the intestine, LCFA-CoA molecules in the hypothalamus activate neural pathways that increase insulin sensitivity in the liver, and they also reduce food intake5–8 (Fig. 1). So LCFA-CoA seem to function acutely as a signal of nutrient abundance, triggering counter-regulatory responses that originate in the brain and the gut to limit further internal and external contributions to blood glucose levels. Unfortunately, both protective mechanisms are quickly inactivated by the ingestion of a fat-rich diet. For example, Wang et al.3 found that the reduction in liver glucose production in response to intestinal lipids ceases after only three days of feeding rats a high-fat diet, and similar observations were made for the brain’s LCFA-CoA sensor 5,6. These results suggest that such diets promote obesity and diabetes in part by impairing nutrient-sensing systems that are 942
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designed to restrict food intake and enhance insulin sensitivity. The apparent fragility of fatty-acid sensors in the intestine and the hypothalamus raises concerns about their ‘real world’ relevance. How important are fat sensors that can be overwhelmed by just three days of high-fat feeding? One hypothesis for the modern-day failure of mechanisms responsible for energy homeostasis posits that these systems evolved during periods of food scarcity and are thus ill-equipped for environments with abundant, palatable food. Moreover, the quantity and type of lipids in modern diets, typically high in saturated fats, might exert different effects from those observed by Wang et al.; the lipid infusions these authors used contained primarily polyunsaturated fats. A chronic surfeit of dietary fat can also reverse the beneficial effects of the acute lipid infusions Wang and colleagues studied. Long-term exposure to dietary lipids increases fatty-acid oxidation, lowering LCFA-CoA levels. Moreover, chronic fat intake causes insulin resistance through weight gain and lipid accumulation in muscle cells. Lastly, compelling evidence indicates9 that prolonged exposure to fatty acids from high-fat feeding and/or obesity stimulates inflammatory pathways that cause insulin resistance, perhaps overriding the acute insulin-sensitizing effects of intestinal lipids. The revelation that intestinal nutrient sensing increases insulin sensitivity could aid our understanding of how bariatric surgery — operations that promote weight loss by modifying the gastrointestinal tract — ameliorates diabetes. A procedure known as Roux-en-Y gastric bypass
surgery causes complete remission of diabetes in 84% of cases10, and increasing evidence indicates11 that this involves mechanisms beyond reductions in food intake and body weight. This operation, which alters the path of nutrients through the small intestine, increases the secretion of incretins. Wang and colleagues’ work raises the untested possibility that complementary effects on the activity of the intestine–brain–liver neural circuit might further improve glucose metabolism. The discovery of incretins led to a new class of antidiabetes drugs exemplified by exenatide. The LCFA-CoA-stimulated intestine–brain– liver circuit also provides potential targets for novel antidiabetes drugs and a conceptual basis for antidiabetes diets. ■ Joshua P. Thaler and David E. Cummings are in the Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Harborview Medical Center and VA Puget Sound Health Care System, 1660 South Columbian Way, S-111-Endo, University of Washington, Seattle, Washington 98108, USA. e-mail:
[email protected] 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Woods, S. C. Psychol. Rev. 98, 488–505 (1991). Drucker, D. J. Cell Metab. 3, 153–165 (2006). Wang, P. Y. T. et al. Nature 452, 1012–1016 (2008). Cummings, D. E. & Overduin, J. J. Clin. Invest. 117, 13–23 (2007). Obici, S. et al. Diabetes 51, 271–275 (2002). Lam, T. K. et al. Nature Med. 11, 320–327 (2005). Obici, S., Feng, Z., Arduini, A., Conti, R. & Rossetti, L. Nature Med. 9, 756–761 (2003). Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. Cell Metab. 1, 53–61 (2005). Wisse, B. E., Kim, F. & Schwartz, M. W. Science 318, 928–929 (2007). Buchwald, H. et al. JAMA 292, 1724–1737 (2004). Cummings, D. E., Overduin, J., Foster-Schubert, K. E. & Carlson, M. J. Surg. Obes. Relat. Dis. 3, 109–115 (2007).
OPTICS
Light reined in Diederik Sybolt Wiersma Light always travels at the same speed in a vacuum, no more, no less. But in materials, there’s room for manoeuvre: tweak the right material in the right way, and exciting optoelectronic properties result. In air, light travels at a speed of about 300,000 kilometres per second. That means it can circle Earth more than seven times in one second — so stupefyingly fast that we generally consider the arrival of light rays to be instantaneous. Finding ways to slow down and control the speed of light has inspired researchers for decades, both because it is fundamentally interesting and because it is potentially of practical use. If you could moderate light’s speed in a material well known for its superior optoelectronic properties — thus giving the light more time to interact and exchange energy with the material— you would be on to a winner. Writing in
Physical Review Letters, Shubina et al.1 describe how they have done just that in gallium nitride. This semiconductor has a wide bandgap such that it emits light at blue wavelengths; is easily ‘doped’ with impurities to create optoelectronic interactions; and is mechanically robust, even at high temperatures. Of the many uses gallium nitride has found in optoelectronic devices, the most cutting-edge is in the blue laser diodes used to read and write high-density Bluray storage discs2. This latest advance from Shubina and colleagues will aid the development of integrated components for optical signal processing, and potentially of detectors and solar cells that use gallium nitride.
