CHARACTERIZATION OF EXPRESSION OF HYPOTHALAMIC APPETITE-REGULATING PEPTIDES IN OBESE HYPERLEPTINEMIC BROWN ADIPOSE TISSUE-DEFICIENT (UNCOUPLING PROTEIN-PROMOTER-DRIVEN DIPHTHERIA-TOXIN-A) MICE
Na. Tritos et al., CHARACTERIZATION OF EXPRESSION OF HYPOTHALAMIC APPETITE-REGULATING PEPTIDES IN OBESE HYPERLEPTINEMIC BROWN ADIPOSE TISSUE-DEFICIENT (UNCOUPLING PROTEIN-PROMOTER-DRIVEN DIPHTHERIA-TOXIN-A) MICE, Endocrinology, 139(11), 1998, pp. 4634-4641
Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driv
en diphtheria toxin A (DTA)I mice develop obesity as a result of both
decreased energy expenditure and hyperphagia. The hyperphagia occurs d
espite high serum leptin levels. Hence, this is a model of leptin-resi
stant obesity in which the mechanism driving hyperphagia is unknown. L
eptin is a regulator of a number of hypothalamic neuropeptides involve
d in energy homeostasis. In ob/ob mice, leptin deficiency results in i
ncreased expression of neuropeptide Y (NPY), agouti-related protein (A
GRP), and melanin-concentrating hormone (MCH), and decreased expressio
n of POMC. We have previously shown that NPY is reduced in the UCP-DTA
mouse, suggesting a normal NPY response to leptin. To define other po
tential sites of leptin resistance, we used in situ hybridization to e
valuate the expression of messenger RNAs (mRNAs) encoding a number of
peptides, including NPY, AGRP, MCH, and POMC. We confirmed that, the d
ecrease in NPY expression previously detected by Northern blots reflec
ts a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was
also decreased, whereas POMC mRNA levels in the arcuate nucleus were t
he same as control. MCH mRNA levels in the lateral hypothalamic area w
ere also decreased. In contrast, there was induction of NPY expression
in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but no
t in the controls. The results indicate that these neuropeptides gener
ally respond to leptin and that the hyperphagia seen in the UCP-DTA mi
ce is likely the result of dysregulated expression of other, as yet un
examined, hypothalamic peptides, or lies at sites distal to the hypoth
alamus.