Nutropioids, Hedonism in the Gut?
Authors: Paul T. Pfluger, Sonja C. Schriever, Matthias H. Tschöp
Journal: Cell Metabolism (2012)

The opioid system plays a pivotal role in how our brain regulates hedonic components of ingestive behavior. Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar add the gut to this opioid landscape, demonstrating direct activation of periportal μ-opioid receptors by food-derived opioid peptides (nutropioids), and a gut-brain feedback spiral that culminates in enhanced satiety. The opioid system plays a pivotal role in how our brain regulates hedonic components of ingestive behavior. Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar add the gut to this opioid landscape, demonstrating direct activation of periportal μ-opioid receptors by food-derived opioid peptides (nutropioids), and a gut-brain feedback spiral that culminates in enhanced satiety. For centuries, everybody—from chocolate lovers to steak aficionado—has agreed on the addictive reward of certain foods. In fact, "food cravings" have been shown to override even the strongest homeostatic drive. Their neuroanatomical and molecular underpinnings suggest striking similarities with central opioidergic mechanisms previously identified to mediate classic drug addictions. Accordingly, opioid receptors in the brain have been shown to orchestrate multiple hedonic components of ingestive behavior. An elegant study recently published in Cell now also introduces the gut as a potential control center for opioid response circuits regulating food intake (Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Opioid control of food intake has been studied for several decades. Endogenous opioid peptides such as endorphins were first identified in 1975 (Hughes, 1975Hughes J. Brain Res. 1975; 88: 295-308Crossref PubMed Scopus (677) Google Scholar). Today, the current model suggests that opioid signaling, especially via the μ-opioid receptor (MOR), is a major driver of both the "wanting" (i.e., incentive motivation and appetite) and "liking" (i.e., pleasure and palatability) aspects of ingestive behavior. "Nutropioids," i.e., opioid oligopeptides derived from food, had also been known for years. However, their physiological relevance remained unclear and controversial (Teschemacher, 2003Teschemacher H. Curr. Pharm. Des. 2003; 9: 1331-1344Crossref PubMed Scopus (175) Google Scholar). Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar demonstrate that satiety effects induced by protein-enriched diets (PED) can be attributed to such nutropioids and opioid antagonism at the level of MORs, which are localized in the periportal neural system (Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). The authors first show MOR-dependent regulation of intestinal gluconeogenesis (IGP) by using portal infusions of MOR effectors in combination with a metabolic glucose tracer in conscious rodents. Immunohistochemical studies reveal the close proximity of MORs and neuronal fibers in the portal vein walls. The authors further observe that MOR antagonist-induced activation of neurons in brain regions, which is implicated in the increased food consumption, is abrogated by capsaicin treatment and vagotomy; infusion of MOR agonists reverses the PED-mediated activation of neurons. The authors further show both in vivo and in vitro that proteolytic digests and selected oligopeptides mainly act as MOR antagonists. Consistent with the notion that MORs control a gut-brain circuit, MOR-knockout mice are insensitive to oligopeptide-induced intestinal gluconeogenesis and PED-mediated satiety. Furthermore, MOR antagonists are unable to induce food intake in glucose-6-phosphatase-deficient mice that lack intestinal gluconeogenesis, supporting the concept that gut glucose can play a key mediatory role (Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Overall, Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar suggest a model (Figure 1) where MOR-regulated food intake depends on a complex spiral feedback that involves release of nutropioids into the portal vein, which in turn antagonizes MOR receptors in periportal neurons. These ascending neurons increase the expression of intestinal gluconeogenic genes via a CNS relay, leading to the release of glucose into portal circulation. Consequently, the increased glucose concentration in portal circulation activates ascending glucose-sensing periportal neurons, which ultimately reduces food intake via hypothalamic nuclei involved in the homeostatic and hedonic regulation of ingestive behavior. Despite the elegance of Duraffourd's model of nutropioid action, multiple questions remain and some new ones emerge. How do changes in dietary macronutrients alter the nutropioid gut-brain circuitry? It would be of interest for instance to examine whether the popular Atkins diet—with its abundance of alimentary protein but low carbohydrate content—exerts some of its anorexigenic and weight-lowering impact through MOR nutropioid ligands. Would there be "nutropioid"-rich and -poor versions of the Atkins diet, and would those have differential effects on adiposity, appetite, and systemic metabolism? Bariatric surgery had been shown to immediately decrease hedonic drive toward hunger (Schultes et al., 2010Schultes B. Ernst B. Wilms B. Thurnheer M. Hallschmid M. Am. J. Clin. Nutr. 2010; 92: 277-283Crossref PubMed Scopus (118) Google Scholar). Could such effects be mediated via changes in nutropioid levels, or via a modulation of signaling events at the level of portal vein MORs? It is particularly intriguing that alimentary peptides seem to act solely as opioid antagonists at portal MORs. Digestion of alimentary proteins will however result in a complex oligopeptide mixture of opioid antagonists and agonists. In fact, most alimentary opioid ligands identified to date, e.g., casomorphin from milk casein or exorphin from gluten, were classified as opioid agonists. Only long-term dietary studies, or chronic portal infusions of defined ratios of MOR agonists versus antagonists, could help to delineate the complexity of nutropioid action. Nutropioids may also activate MORs residing within the gut mucosal layer in a similar fashion as the gut hormone cholecystokinine (CCK), which has been show to induce intestinal glucose production after intraduodenal infusion (Breen et al., 2011Breen D.M. Yue J.T.Y. Rasmussen B.A. Kokorovic A. Cheung G.W.C. Lam T.K.T. Diabetes. 2011; 60: 3148-3153Crossref PubMed Scopus (27) Google Scholar). Nutropioid action might further not be restricted to periportal MORs, but could also involve δ- or κ-opioid receptors, which have been implicated in the regulation of food reward and food addiction (Gosnell et al., 1986Gosnell B.A. Levine A.S. Morley J.E. Life Sci. 1986; 38: 1081-1088Crossref PubMed Scopus (135) Google Scholar). An intriguing possibility finally arises from recent studies that support a major role for gut microbiota in the etiology of obesity (Turnbaugh et al., 2006Turnbaugh P.J. Ley R.E. Mahowald M.A. Magrini V. Mardis E.R. Gordon J.I. Nature. 2006; 444: 1027-1031Crossref PubMed Scopus (8177) Google Scholar). Could certain species of gut bacteria produce microbial opioids, or facilitate conversion of alimentary oligopeptides into potent MOR ligands? Microbial MOR agonists have been identified before, such as the ultrapotent dermorphins or deltorphins, opioid agonists up to 40 times more potent than morphine that have been isolated from the skin of giant leaf frogs of the genus Phyllomedusa. Albeit highly speculative, such a potential interaction of our gut flora and the nutropioid gut-brain circuitry could add interesting future perspectives to an already fascinating research field. The work by Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar may not replace the currently accepted, classical model of opioidergic food intake control, which suggests the central release of endogenous opioids as the major stimulus for a hedonic drive to consume food. Nonetheless, Duraffourd et al., 2012Duraffourd C. De Vadder F. Goncalves D. Delaere F. Penhoat A. Brusset B. Rajas F. Chassard D. Duchampt A. Stefanutti A. et al.Cell. 2012; 150: 377-388Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar expand a CNS-centric view to a model that also allows direct peripheral action of alimentary opioid antagonists on periportal MORs, followed by the (IGP-dependent) decrease in food consumption. The strength of this new model lays in the integration of both worlds; direct effects of alimentary "nutropioids" could be followed by—or compete—with a concomitant increase in endogenous opioids, such as β-endorphin (which could be released by both the GI tract and the CNS). Thus, exogenous and endogenous opioids could orchestrate hedonic feeding mechanisms at multiple sites, both in the periphery and in the CNS. Mu-Opioid Receptors and Dietary Protein Stimulate a Gut-Brain Neural Circuitry Limiting Food IntakeDuraffourd et al.CellJuly 5, 2012In BriefDietary proteins lead to lasting satiety by interacting with opioid receptors on nerves in the portal vein, which drains blood from the gut. Resulting signals to the brain are transmitted back to the gut to stimulate intestinal gluconeogenesis, which curbs appetite. Full-Text PDF Open Archive