Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

An invariant spatial pattern of three cell fates (3 degrees-3 degrees-2 degrees-1 degree-2 degrees-3 degrees) is generated from a field of multipotent precursor cells during C. elegans vulval development. We demonstrate that the epidermal growth factor-like domain of the LIN-3 protein can induce either of two distinct vulval cell fates: a high dose of LIN-3 induces a 1 degree fate; a lower dose of LIN-3 induces a 2 degrees fate. A high dose of LIN-3 can also induce adjacent vulval precursor cells to assume 1 degree fates; thus, high levels of LIN-3 can override the lateral signaling that normally inhibits formation of adjacent 1 degree fates. We propose that the invariant pattern of vulval cell fates is generated by a graded distribution of LIN-3 that promotes different vulval fates according to local concentration and by a lateral signal that reinforces this initial bias.

Wnt proteins are intercellular signals that regulate various aspects of animal development. In Caenorhabditis elegans, mutations in lin-17, a Frizzled-class Wnt receptor, and in lin-18 affect cell fate patterning in the P7.p vulval lineage. We found that lin-18 encodes a member of the Ryk/Derailed family of tyrosine kinase-related receptors, recently found to function as Wnt receptors. Members of this family have nonactive kinase domains. The LIN-18 kinase domain is dispensable for LIN-18 function, while the Wnt binding WIF domain is required. We also found that Wnt proteins LIN-44, MOM-2, and CWN-2 redundantly regulate P7.p patterning. Genetic interactions indicate that LIN-17 and LIN-18 function independently of each other in parallel pathways, and different ligands display different receptor specificities. Thus, two independent Wnt signaling pathways, one employing a Ryk receptor and the other a Frizzled receptor, function in parallel to regulate cell fate patterning in the C. elegans vulva.