Abnormal cholinergic and GABAergic vascular innervation in the hypothalamic arcuate nucleus of obese tub/tub mice.
Tubby and tubby-like proteins (TULPs) are encoded by members of a small gene family. An autosomal recessive mutation in the mouse tub gene leads to blindness, deafness, and maturity-onset obesity. The mechanisms by which the mutation causes the obesity syndrome has not been established. We compared obese tub/tub mice and their lean littermates in order to find abnormalities within the mediobasal hypothalamus, a region intimately associated with the regulation of body weight. Using an antiserum to the vesicular acetylcholine transporter (VAChT), a marker for cholinergic neurons, many unusually large VAChT-immunoreactive (-ir) nerve terminals, identified by colocalization with the synaptic vesicle protein synaptophysin, were demonstrated in the hypothalamic arcuate nucleus of obese tub/tub mice. Double-labeling showed that VAChT-ir nerve endings also contained glutamic acid decarboxylase (GAD), a marker for gamma-aminobutyric acid (GABA) neurons. The VAChT- and GAD-ir nerve terminals were in close contact with blood vessels, identified with antisera to platelet endothelial cell adhesion molecule-1 (PECAM; also called CD31), laminin, smooth muscle actin (SMA), and glucose transporter-1 (GLUT1). Such large cholinergic and GABAergic nerve terminals surrounding blood vessels were not seen in the arcuate nucleus of lean tub/+ mice. The presence of abnormal cholinergic/GABAergic vascular innervation in the arcuate nucleus suggests that alterations in this region, which contains neurons that receive information from the periphery and which relays information about the energy status to other parts of the brain, may be central in the development of the obese phenotype in animals with an autosomal recessive mutation in the tub gene.
Bäckberg
Matilda
M
Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Meister
Björn
B
D000109:Acetylcholine / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000098:blood supply / Q000378:metabolism*; D001808:Blood Vessels / Q000294:innervation; D002352:Carrier Proteins / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry; D026901:Membrane Transport Proteins; D051379:Mice; D009154:Mutation; D009765:Obesity / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D017729:Presynaptic Terminals / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D016708:Synaptophysin / Q000378:metabolism; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D011506:Proteins; C493460:Slc18a3 protein, mouse; D016708:Synaptophysin; C098988:Tub protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; D000109:Acetylcholine