Loss of enteroendocrine cells in mice alters lipid absorption and glucose homeostasis and impairs postnatal survival

Abstract

At least 10 enteroendocrine cell types have been identified, and the peptide hormones they secrete have diverse functions that include regulation of glucose homeostasis, food intake, and gastric emptying. Mice lacking individual enteroendocrine hormones, their receptors, or combinations of these have shed light on the role of these hormones in the regulation of energy homeostasis. However, because enteroendocrine hormones have partially overlapping functions, these loss-of-function studies produced only minor phenotypes, and none of the enteroendocrine hormones was shown to be essential for life. To examine the effect of loss of all enteroendocrine cells and hormones on energy homeostasis, we generated mice with intestinal-specific ablation of the proendocrine transcription factor neurogenin 3 (referred to herein as Ngn3 Δint mice). Ngn3 Δint mice were deficient for all enteroendocrine cells and hormones, and died with a high frequency during the first week of life. Mutant mice were growth retarded and had yellowish stool suggestive of steatorrhea. Subsequent analyses revealed that Ngn3 Δint mice had impaired lipid absorption, reduced weight gain, and improved glucose homeostasis. Furthermore, intestinal epithelium of the mutant mice showed an enlarged proliferative crypt compartment and accelerated cell turnover but no changes to goblet and Paneth cell numbers. Enterocytes had shorter microvilli, but the expression of the main brush border enzymes was unaffected. Our data help unravel the role of enteroendocrine cells and hormones in lipid absorption and maintenance of the intestinal epithelium.

Lmx1a functions in intestinal serotonin-producing enterochromaffin cells downstream of Nkx2.2

“…Δint mice are severely growth retarded, frequently die in the first week after birth, have a smaller intestine and have improved glucose clearance (Mellitzer et al, 2010). We postulate that the differences in metabolic phenotypes between these two mouse models might be attributed to the hormone Ghrl, which is highly upregulated in the Nkx2.2 Δint mice (this study), but downregulated in the Ngn3…”

“…The transient increase in length of the small intestine of 6-weekold Nkx2.2 Δint mice, as opposed to the decrease seen in the Ngn3 Δint mice (Mellitzer et al, 2010), is also of interest. The increased length could be due to compensatory intestinal growth as an adaptive response to the alteration of gut hormone expression.…”

Generation of enteroendocrine cell diversity in midgut stem cell lineages

“…Indeed, carcinoid tumors are neuroendocrine malignancies that secret hormones, which cause debilitating symptoms in patients. In addition, loss of endocrine cell subtypes has been associated with metabolic disruptions, including lipid absorption and glucose homeostasis (Mellitzer et al, 2010). Our study suggests that these effects might result from either the loss of specific peptides or overabundance of others in the diffuse endocrine system.…”

Functional Regulation of Sugar Assimilation by N-Glycan-specific Interaction of Pancreatic α-Amylase with Glycoproteins of Duodenal Brush Border Membrane

“…Bound PPA was little incorporated into the enterocytes at 4°C. To confirm that PPA bound to the BBM in the duodenum, the immunolocalizations of the marker enzymes for BBM of enterocytes, SI and SGLT1 (20), were compared. As shown in Fig.…”