Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production

Blood glucose regulation The mere presence of lipids in the intestine is known to reduce nutrient intake in both rodents and humans by activating the intestine–brain neural axis. More recently, studies have indicated that the brain senses blood lipids directly to inhibit glucose production and maintain glucose homeostasis in rodents through a brain–liver neural axis. Now comes the first demonstration that upper intestinal lipids rapidly inhibit glucose production through an intestine–brain–liver neurocircuit. Work in rats shows that the lipids or fats which enter the small intestine trigger the afferent neuronal signal to the brain, which then sends signals to the liver to lower glucose production and blood glucose levels in as little as fifteen minutes. But eating a high-fat diet for just three days can interfere with this signal, disabling it so that it does not signal the other organs to lower blood glucose levels. This holds out the prospect that novel sites and targets may be revealed to lower glucose or blood sugar levels in those who are obese or have diabetes. The presence of lipids in the intestine causes a reduction in nutrient intake, but it is now shown that lipids present in the intestine also regulate endogenous nutrient production. According to the data, putative intra-intestinal lipid sensors signal the presence of ingested lipids, via the brain, to the liver, which reduces the endogenous glucose production accordingly. Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine–brain axis 1 , 2 , 3 , 4 . In parallel, a brain–liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents 5 . Thus, we tested the hypothesis that upper intestinal lipids activate an intestine–brain–liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in