Unexpected systemic phenotypes result from focal combined deficiencies of forebrain insulin receptor/IGF-1 receptor signaling

Abstract

Midlife obesity has recently been identified as a global pandemic (1). Morbidities and mortalities attributable to excess adiposity include atherosclerosis, type 2 diabetes (T2D) (2), certain cancers (3), and dementia (4), each of which has reached epidemic proportions on its own. It is no exaggeration to state that T2D and dementia threaten the emotional and financial stabilities of most Western economies. Moreover, when T2D and dementia comorbidity is present, the severities and costs of management of each are dramatically increased (5). Thus, there are major imperatives that drive current inquiries into the borderland where cognition and metabolism intersect. New research in PNAS by Soto et al. (6) provides significant insight into this area by describing dramatic links to phenotypes relevant to cognition, behavior, and metabolism. A key set of principles drove this work: ( i ) insulin receptors (IRs) and insulin-like growth factor 1 (IGF-1) receptors (IGF1Rs), upon binding of their cognate ligand, trigger two closely related signaling pathways that promote both redundant and distinct intracellular effects (7), and ( ii ) this redundancy includes the formation of IR/IGF1R hybrids, and it has been estimated that at least half of the IRs and IGF1Rs in brain exist as heterodimers (8), which have greatest affinity for IGF-1 and IGF-2 (Fig. 1).\n\n\n\nFig. 1. \nFocal forebrain IR/IGF1R DKO eliminates signaling by receptor homodimers and hybrids in hippocampus or central amygdala. ( A ) Focal forebrain IR/IGF1R DKO eliminates homodimers and IR/IGF1R heterodimers and precludes distinct and collateral insulin, IGF-1, and IGF-2 signaling via these receptors. HR, IR/IGF1R hybrid receptors; IRS, insulin receptor substrate. ( B ) Targeted DKO in forebrain causes dramatic region-specific phenotypes. Hippo-DKO mice show anxiety, learning behavior deficits, and glucose intolerance, while CeA-DKO mice show defective thermogenesis … \n\n\n\n[↵][1]1To whom correspondence should be addressed. Email: samuel.gandy{at}mssm.edu.\n\n [1]: #xref-corresp-1-1