Diabetes is a devastating metabolic disease affecting over 220 million people worldwide. If left untreated, diabetes can disrupt the physiology of all major organ systems. Type 2 diabetes (T2D), the most prevalent form, is a multi-factorial disease with the early stages often characterized by lost insulin sensitivity. Many environmental factors and genes are associated with an increased risk for T2D, but the molecular pathways that are directly affected by these risk factors are largely unknown. Identification of and intervention along these pathways should enable the development of effective preventative treatments.

The lipid phosphatase SHIP2 (SH2-domain-containing inositol phosphatase 2) has been found to influence both insulin sensitivity and diet-induced obesity, which are key factors contributing to T2D. As a result, SHIP2 is a potential therapeutic target for the treatment of T2D, but the molecular pathway it controls has not been identified. These unknowns make it difficult to identify inroads for intervention and to predict the possible side effects associated with SHIP2 modification. This study investigates the molecular mechanism of SHIP2 function.

This study uses loss-of-function analysis in the zebrafish embryo to determine the primary signaling pathway(s) that require SHIP2 function. In the zebrafish model, developmental defects and changes in gene expression help identify pathways that are influenced by genetic modifications. In the early zebrafish embryo, inhibition of SHIP2 expression resulted in defective patterning of tissue precursors. Direct analysis of activated signaling and the expression of downstream gene targets indicated that embryos lacking SHIP2 had elevated fibroblast growth factor (FGF) signaling.

The FGF pathway operates in conjunction with other signaling pathways, such as bone morphogenetic proteins (BMP), to regulate gene expression, replication and differentiation. The expanded FGF signaling in the pre-gastrula zebrafish embryo created an abnormal dorsoventral gradient of BMP activity, which altered tissue patterning. This work demonstrates that SHIP2 functions intracellularly, downstream of the FGF receptor, to attenuate FGF signaling. Changes in FGF signaling have been associated with diabetes and related metabolic disorders.

This study demonstrates that, in vivo, SHIP2 is a downstream effector of the FGF receptor that provides ‘feedback’ to attenuate FGF signaling. Although it is possible that SHIP2 may be affected by additional signaling pathways to influence metabolic homeostasis, FGF signaling could account for many characteristics of the SHIP2 loss-of-function phenotype in the mouse, including skeletofacial anomalies and resistance to high-fat diet-induced obesity. The authors postulate that SHIP2 may have a principal role in attenuating signaling through the endocrine FGFs, FGF19 and/or FGF21, which are implicated in diabetes.

2010