The Hypothalamus and β-Cell Connection in the Gene-Targeting Era
- From the Department of Medicine, Division of Endocrinology, Metabolism and Nutrition, School of Medicine, University of Washington, and the Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington.
- Corresponding author: Michael W. Schwartz, , or Vincenzo Cirulli, .
After years of debate, Le Douarin's elegant work (1) established that pancreatic islet cells differentiate from progenitors emerging from the definitive gut endoderm rather than from neuroectoderm as had been inferred from co-expression of neuronal markers. Although islet cells and the brain do not share a common developmental origin, a fascinating picture has emerged in which they nonetheless share many biochemical pathways and, hence, are characterized by extensive overlap in gene expression. Brain and islet are also tightly linked functionally through neural-entero-islet, brain-islet, and islet-brain axes (2,3). Thus, the secretion of insulin and other islet hormones are clearly regulated by the hypothalamus and other brain areas, while conversely insulin action in the hypothalamus influences both energy balance (4) and glucose metabolism (5). Not surprisingly, therefore, targeted deletion or induction of genes in either tissue can yield mice with overlapping phenotypes where hormone secretion and glucose metabolism are concerned. The report by Wicksteed et al. (6) in this issue of Diabetes sheds welcome light on the extent to which commonly used mouse models for β-cell–specific gene targeting affect gene expression in the brain as well as in the islet.
A commonly employed strategy for gene targeting in vivo employs the Cre/LoxP system of DNA recombination that allows for either deletion or de novo induction of select gene-coding sequences in specific cell types in mice (7–9). Tissue specificity with this method is achieved through the use of cell type-specific promoters to drive expression of Cre recombinase, an enzyme that cleaves DNA sequences between flanking LoxP sites. These promoters can be further modified to incorporate drug-responsive elements, allowing Cre recombinase expression to be switched on at will …