Gut Hormones Can Mimic Food Effects On Brain
Hunger and satiety are mediated by a range of peripheral signals to the brain. A new study by Akila de Silva and colleagues from Imperial College London, UK, published in Cell Metabolism, shows that infusion of two gut hormones can reduce food intake and mimic the central effects of a meal in humans. Specifically, the researchers used functional magnetic resonance imaging (fMRI) to examine the effect of infusing the gut hormones PYY(3-36) and GLP-1(7-36 amide) on brain activation with presentation of food-salient images in six brain regions known to be involved in ingestive behaviour (amygdala, caudate, insula, nucleus accumbens, orbitofrontal cortex, and putamen) of 16 young normal-weight volunteers. In addition, the researchers looked at the effect of these gut hormones on hunger and eating behaviour before and after a standardized breakfast and an ad libitum buffet lunch. Combined infusion of these hormones not only led to similar activation/suppression of brain regions as seen after the standardized meal, but also reduced subsequent energy intake. Not only does this study provide further insight into how the gut talks to the brain but also provides evidence for the involvement of these hormones in ingestive behaviour. Whether or not such insights can be harnessed to provide better treatments for obesity remains to be seen. AMS San Francisco, CA p.s. Hat tip to Bill Colmers for alerting me to this article De Silva A, Salem V, Long CJ, Makwana A, Newbould RD, Rabiner EA, Ghatei MA, Bloom SR, Matthews PM, Beaver JD, & Dhillo WS (2011). The Gut Hormones PYY(3-36) and GLP-1(7-36 amide) Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans. Cell metabolism, 14 (5), 700-6 PMID: 22000927
Central Effects of GLP-1 Analogues
Yesterday, I discussed how part of the improvements in type 2 diabetes patients after gastric bypass surgery may be due to increased postprandial release of GLP-1. However, it is becoming increasingly apparent that GLP-1 also exerts central effects on hunger and satiety, and perhaps even affects the desire for certain foods. Therefore, not surprisingly, GLP-1 analogues, while already available for treating diabetes, are currently being investigated for the treatment of obesity. This topic was recently reviewed by Torekov and colleagues from the University of Denmark, in a paper published in Obesity Reviews. As the authors note, GLP-1 receptors are expressed in many regions of the brain and in particular in the arcuate nucleus and other hypothalamic regions involved in the regulation of food intake. Animal studies have confirmed that GLP-1’s has central effects on hunger and satiety that are independent of its peripheral effects on glucose metabolism. However, whether peripherally injected GLP-1 actually makes it into the human brain, as suggested by some animal studies, is still a matter of debate. It is also possible that some of the effects of GLP-1 agonists on food intake may be mediated by interaction with sensory afferent neurones of the vagus nerves in the gastrointestinal tract. The notion that GLP-1 analogues may affect feeding even when they do not enter the brain is supported by studies showing that large molecular size GLP-1 receptor agonists (albumin-conjugated GLP-1 receptor agonists), that cannot cross the blood-brain barrier can inhibit feeding in both humans and mice. Thus, it appears that GLP-1 analogues may affect feeding behaviour both through central and peripheral effects. As a side note, it may be of interest that while the ‘hunger hormone’ ghrelin appears to counteract (or rather override) the effects of GLP-1 on satiety, the commonly used anti-diabetic drug metformin appears to increase expression of GLP-1 receptors and enhance GLP-1 secretion and sensitivity in both rodents and humans. Currently, the long-acting GLP-1 analogues exenatide and liraglutide are being investigated as potential anti-obesity drugs, with early indications that this may indeed be worthwhile. Thus, for example, as noted by the authors, in one study with liraglutide, obese subjects in the quartile of greatest weight loss had a mean weight loss of 18 kg with 3.0 mg of liraglutide compared with only 9 kg on placebo. Overall, the authors conclude that: “The recognition that several gastrointestinal hormones, released in response to nutritional stimuli are… Read More »
Role Of GLP-1 In The Resolution of Diabetes After Gastric Bypass Surgery
Yesterday, I discussed the strong interest in trying to understand why exactly bariatric surgery leads to an often dramatic improvement (if not resolution) of type 2 diabetes. Additional insights into this topic comes from Marzieh Salehi and colleagues in a paper just published in Diabetes. The paper takes advantage of the fact that some patients undergoing gastric bypass (GB) surgery experience significantly increased insulin secretion following a meal, sometimes even resulting in clinically significant hypoglycaemia. In order to test the hypothesis that this increase in insulin secretion is in part mediated by the incretin glucagon-like peptide 1 (GLP-1), asymptomatic individuals with previous GB, 10 matched healthy nonoperated control subjects, and 12 patients with recurrent hypoglycemia after GB were examined with and without administration of the GLP-1 receptor antagonist exendin-(9-39). Blocking GLP-1 significantly reduced postprandial insulin secretion in GB patients than in the non-surgical controls. However, in the hypoglycaemic GB patients, GLP-1 appeared to account for about 45% of increased insulin secretion, not much more than in the non-hypoglycemic surgical subjects. Glucagon was suppressed similarly by hyperglycemia in all groups but rose significantly after the meal in surgical individuals but remained suppressed in nonsurgical subjects. GLP-1 receptor blockade increased postprandial glucagon in both surgical groups. As the authors conclude, “Increased GLP-1-stimulated insulin secretion contributes significantly to hyperinsulinism in GB subjects. However, the exaggerated effect of GLP-1 on postprandial insulin secretion in surgical subjects is not significantly different in those with and without recurrent hypoglycaemia.” This means that additional factors are probably involved in the hypoglycaemic response seen in some GB patients. As pointed out in an accompanying editorial by Jens Juul Holst, however, these findings may be more difficult to interpret due to several features of the study design used by Salehi and colleagues. Thus, without going into too many methodological details, there are questions about whether or not the approach used in this study fully explored (or rules out) the role of GLP-1 in the hypoglycaemic response. Nevertheless, the study certainly supports the notion that increased secretion of GLP-1 following GB surgery, together with other mechanisms including secretion of other enteric hormones, quicker passage of food through the small bowel, reduction in liver fat, and weight loss in general, may all play a role in the substantial glycemic improvements seen with GB surgery in patients with type 2 diabetes. Thus, while administration of GLP-1 analogues can potentially mimic some of… Read More »
GLP-1 Receptor Agonists, Obesity And Psoriasis
I have previously discussed the not too uncommon association between obesity and psoriasis, a chronic, autoimmune disease that causes red, scaly patches to appear on the skin, and affects 2-3% of the population in Western countries. Hogan and colleagues, St Vincent’s University Hospital, University College Dublin, Ireland, in a paper just published in Diabetologia, now report improvement of psoriasis in three obese patients with type 2 diabetes several weeks after the initiation of therapy with the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists exenatide and liraglutide. Regular readers may recall that GLP-1 receptor agonists were recently introduced for the treatment of diabetes and are currently under investigation for the treatment of obesity. In addition to the clinical improvement, with reduced itching and/or a reduction in Psoriasis Area and Severity Index (PASI) scores, they also provide evidence that GLP-1 receptor agonist treatment had immunological effects in that it increased the number of natural killer T (NKT) cells in the circulation and reduced the number of invariant NKT cells in the psoriatic plaques. In an accompanying commentary, Drucker and Rosen from the University of Toronto, point out that apart from the ‘classical’ metabolic effects of GLP-1 (e.g. on the secretion of insulin and glucagon), GLP-1 receptors are also found in numerous immune cell subpopulations, including thymoyctes, splenocytes, bone marrow-derived cells, and regulatory T cells. It is therefore biologically ‘plausible’ that administration of GLP-1 analogues could have anti-inflammatory effects on psoriasis (and perhaps other inflammatory abnormalities). Obviously, a few cases do not yet make an indication, but they certainly suggest that this hypothesis may well be worthy of further study. I certainly wonder, if any of my readers have experienced similar improvements in inflammatory conditions like psoriasis with the use of GLP-1 analogues. AMS Edmonton, Alberta Hogan AE, Tobin AM, Ahern T, Corrigan MA, Gaoatswe G, Jackson R, O’Reilly V, Lynch L, Doherty DG, Moynagh PN, Kirby B, O’Connell J, & O’Shea D (2011). Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis. Diabetologia PMID: 21744074 Drucker DJ, & Rosen CF (2011). Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology. Diabetologia PMID: 21892687
How Your Gut Feeds Your Fat Addiction
Have you ever wondered why it is almost impossible to only eat one potatoe chip or French fry? Regular readers may recall a previous post on the discovery that we have specific oral sensory receptors that allow us to sense the ‘fattiness’ of food – a function that makes a lot of sense, given that dietary fat provides the densest source of caloric intake. Now, Nicholas DiPatrizio and colleagues from the University of California, Irvine, have discovered that these oral dietary fat sensors activate a powerful ‘addiction-type’ mechanism in your gut that serves to promote further fat intake – their study is published in a recent issue of the Proceedings of the US National Academy of Science. For their studies, the researchers used a well established ‘sham feeding’ model in the rat, where liquid diets eaten by the animal can be drained from the stomach via a chronically implanted gastric cannula, thereby preventing them from reaching the small intestines. Using this model, the researchers showed that ‘sham feeding’ of a high-fat diet resulted in the potent activation of endocannabinoids in the early part of the small intestine by altering enzymatic activities that control endocannabinoid metabolism. The endocannbinoids (cannabis-like compounds produced in the body) are well known to play an important role in regulating ‘rewarding’ feeding behaviours. This effect was abolished by surgical transection of the vagus nerve showing that the stimulation of these changes in the gut is driven through a centrally mediated neuronal pathway. Furthermore, the local application of cannabinoid type 1 receptors blockers (e.g. rimonabant) in the small gut, reduced increased sham fat ingestion. In other words, this study shows that oral sensing of fat sends a signal to the brain, which in turn sends a signal to the gut leading to formation of endocannabinoids, which in turn re-enforce fat eating. This is probably why, just eating one piece of fatty food (say one potatoe chip or French fry) is so hard – simply eating one makes you want to continue eating till the whole bag or plate is empty. Unfortunately, the drug rimonabant, used to effectively block this effect in this study, is no longer available for obesity management (it was withdrawn due to its negative impact on mood), but it may well be that other CB-1 inhibitors that do not enter the brain may prove to be effective to reduce fat intake. Or, in the words… Read More »
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