INVESTIGADORES
GOLDSTEIN RAIJ Jorge
artículos
Título:
Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone.
Autor/es:
SANCHEZ VC, GOLDSTEIN J, STUART RC, HOVANESIAN V, HUO L, MUNZBERG H, FRIEDMAN TC, BJORBAEK C, NILLNI EA.
Revista:
JOURNAL OF CLINICAL INVESTIGATION
Editorial:
American Society for Clinical Investigation
Referencias:
Año: 2004 vol. 114 p. 357 - 369
ISSN:
0021-9738
Resumen:
Regulation of energy balance by leptin involves regulation of several
neuropeptides, including thyrotropin-releasing hormone (TRH).
Synthesized from a larger inactive precursor, its maturation requires
proteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2).
Since this maturation in response to leptin requires prohormone
processing, we hypothesized that leptin might regulate hypothalamic PC1
and PC2 expression, ultimately leading to coordinated processing of
prohormones into mature peptides. Using hypothalamic neurons, we found
that leptin stimulated PC1 and PC2 mRNA and protein expression and also
increased PC1 and PC2 promoter activities in transfected 293T cells.
Starvation of rats, leading to low serum leptin levels, decreased PC1
and PC2 gene and protein expression in the paraventricular nucleus
(PVN) of the hypothalamus. Exogenous administration of leptin to fasted
animals restored PC1 levels in the median eminence (ME) and the PVN to
approximately the level found in fed control animals. Consistent with
this regulation of PCs in the PVN, concentrations of TRH in the PVN and
ME were substantially reduced in the fasted animals relative to the fed
animals, and leptin reversed this decrease. Further analysis showed
that proteolytic cleavage of pro-thyrotropin-releasing hormone (proTRH)
at known PC cleavage sites was reduced by fasting and increased in
animals given leptin. Combined, these findings suggest that
leptin-dependent stimulation of hypothalamic TRH expression involves
both activation of trh transcription and stimulation of PC1 and PC2
expression, which lead to enhanced processing of proTRH into mature TRH.