Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice.
A mutation in the mouse tub gene causes a phenotype characterized by maturity-onset obesity, blindness and deafness. The role of the intact tubby protein and the pathogenesis resulting in the phenotype of tub/tub mice remain largely unknown. In this study, we have investigated whether obese tub/tub mice exhibit altered expression levels for agouti-related protein (AGRP) or glutamic acid decarboxylase-65 (GAD65) in body weight-regulating neurons of the hypothalamic arcuate nucleus. In situ hybridization revealed that AGRP, but not GAD65 mRNA levels, were significantly lower in obese tub/tub mice as compared to tub/+ mice. The lower levels of AGRP mRNA in the arcuate nucleus of tub/tub mice were paralleled by lower fluorescence intensity and numbers of AGRP- and neuropeptide Y (NPY)-immunoreactive (ir) nerve fibers and terminals in the arcuate, ventromedial, dorsomedial hypothalamic nuclei and perifornical and lateral hypothalamic areas. No obvious differences in GAD65-ir nerve fibers and terminals could be detected. Measurements of daily food intake revealed that tub/tub mice displayed progressively higher food consumption as compared to lean tub/+ littermates over a 15-day observation period. When moved to an unfamiliar environment, e.g. a novel cage, daily food intake was initially lower in tub/tub mice than in tub/+ mice suggesting that tub/tub mice may be more sensitive to psychogenic stress. The results together show that tub/tub mice are hyperphagic and exhibit, within the hypothalamic arcuate nucleus, a depressed expression of neuropeptides involved in the regulation of feeding behavior.
Bäckberg
M
M
Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Madjid
N
N
Ogren
S O
SO
Meister
B
B
D048868:Adaptor Proteins, Signal Transducing; D054369:Agouti-Related Protein; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000378:metabolism*; D015536:Down-Regulation; D004435:Eating; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009765:Obesity / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D013315:Stress, Psychological
D048868:Adaptor Proteins, Signal Transducing; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D011506:Proteins; D012333:RNA, Messenger; C098988:Tub protein, mouse; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2