Abstract
The enterohormone glucagon-like peptide-1 (GLP-1) is required to amplify glucose-induced insulin secretion that facilitates peripheral glucose utilisation. Alteration in GLP-1 secretion during obesity has been reported but is still controversial. Due to the high adaptability of intestinal cells to environmental changes, we hypothesised that the density of GLP-1-producing cells could be modified by nutritional factors to prevent the deterioration of metabolic condition in obesity. We quantified L-cell density in jejunum samples collected during Roux-en-Y gastric bypass in forty-nine severely obese subjects analysed according to their fat consumption. In mice, we deciphered the mechanisms by which a high-fat diet (HFD) makes an impact on enteroendocrine cell density and function. L-cell density in the jejunum was higher in obese subjects consuming >30 % fat compared with low fat eaters. Mice fed a HFD for 8 weeks displayed an increase in GLP-1-positive cells in the jejunum and colon accordingly to GLP-1 secretion. The regulation by the HFD appears specific to GLP-1-producing cells, as the number of PYY (peptide YY)-positive cells remained unchanged. Moreover, genetically obese ob/ob mice did not show alteration of GLP-1-positive cell density in the jejunum or colon, suggesting that obesity per se is not sufficient to trigger the mechanism. The higher L-cell density in HFD-fed mice involved a rise in L-cell terminal differentiation as witnessed by the increased expression of transcription factors downstream of neurogenin3 (Ngn3). We suggest that the observed increase in GLP-1-positive cell density triggered by high fat consumption in humans and mice might favour insulin secretion and therefore constitute an adaptive response of the intestine to balance diet-induced insulin resistance.
Highlights
The enterohormone glucagon-like peptide-1 (GLP-1) is required to amplify glucose-induced insulin secretion that facilitates peripheral glucose utilisation
After 2 and 8 weeks of the diet, fasted blood glucose was higher in high-fat diet (HFD) mice than in control diet (CD) mice (P < 0·001 and P < 0·01, respectively (Table 3), and the oral glucose tolerance test (OGTT) revealed as expected a gradual glucose intolerance
Glucose-induced insulin secretion rose in both CD and HFD mice, and the increase above basal level in the HFD mice was twice that observed in the CD mice after 2 and 8 weeks of diet
Summary
The enterohormone glucagon-like peptide-1 (GLP-1) is required to amplify glucose-induced insulin secretion that facilitates peripheral glucose utilisation. We suggest that the observed increase in GLP-1-positive cell density triggered by high fat consumption in humans and mice might favour insulin secretion and constitute an adaptive response of the intestine to balance diet-induced insulin resistance. The crucial role of intestinal hormones has been established in the control of food intake, energy expenditure, glucose homeostasis, lipid metabolism and a wide range of other metabolic functions[1,2] This is illustrated by the phenotype of mice with total loss of enteroendocrine cells, which show growth retardation and high mortality at weaning[3]. It is well established that L-cells are equipped to detect nutrients such as carbohydrates and lipids[7] and their specific distribution along the gut from the absorptive small intestine to the microbiota-colonised large intestine highlights multiple possible controls by nutrients
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