Abstract
ProSAAS is the precursor of a number of peptides that have been proposed to function as neuropeptides. Because proSAAS mRNA is highly expressed in the arcuate nucleus of the hypothalamus, we examined the cellular localization of several proSAAS-derived peptides in the mouse hypothalamus and found that they generally colocalized with neuropeptide Y (NPY), but not α-melanocyte stimulating hormone. However, unlike proNPY mRNA, which is upregulated by food deprivation in the mediobasal hypothalamus, neither proSAAS mRNA nor proSAAS-derived peptides were significantly altered by 1–2 days of food deprivation in wild-type mice. Furthermore, while proSAAS mRNA levels in the mediobasal hypothalamus were significantly lower in Cpefat/fat mice as compared to wild-type littermates, proNPY mRNA levels in the mediobasal hypothalamus and in other subregions of the hypothalamus were not significantly different between wild-type and Cpefat/fat mice. Intracerebroventricular injections of antibodies to two proSAAS-derived peptides (big LEN and PEN) significantly reduced food intake in fasted mice, while injections of antibodies to two other proSAAS-derived peptides (little LEN and little SAAS) did not. Whole-cell patch clamp recordings of parvocellular neurons in the hypothalamic paraventricular nucleus, a target of arcuate NPY projections, showed that big LEN produced a rapid and reversible inhibition of synaptic glutamate release that was spike independent and abolished by blocking postsynaptic G protein activity, suggesting the involvement of a postsynaptic G protein-coupled receptor and the release of a retrograde synaptic messenger. Taken together with previous studies, these findings support a role for proSAAS-derived peptides such as big LEN as neuropeptides regulating food intake.
Highlights
Peptides play major roles in diverse physiological functions, including as hormones, neurotransmitters, and growth factors [1,2]
Images of the arcuate nucleus immunostained for both PEN-LEN and neuropeptide Y (NPY) showed considerable colocalization of these two peptides (Figure 2). These results indicate that some cells in the hypothalamus produce both proSAAS-derived peptides and NPY
The major finding of the present study is that proSAAS-derived peptides have properties consistent with a function as neuropeptides involved in the regulation of feeding
Summary
Peptides play major roles in diverse physiological functions, including as hormones, neurotransmitters, and growth factors [1,2]. Bioactive peptides are typically produced by cleavage of larger precursor proteins at specific sites containing basic residues, often in pairs such as Arg-Arg or Lys-Arg [3,4]. Endopeptidases such as prohormone convertase (PC) 1/3 and 2 cut the precursors at these sites, generating intermediate peptides with C-terminal basic amino acid extensions [5,6]. This approach identified the processing intermediates of many previously characterized neuroendocrine peptides as well as several novel peptides Five of these novel peptides were named based on primary amino acid sequences contained within the larger peptides: big SAAS, little SAAS, PEN, big LEN, and little LEN. The involvement of CPE in the biosynthesis of proSAAS-derived peptides indicates that these peptides are processed in the regulated secretory pathway of neuroendocrine cells
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