Abstract
To address the possible involvement of VGF peptides in obesity and diabetes, we studied type 2 diabetes (T2D) and obese patients, and high-fat diet induced obese mice. Two VGF peptides (NAPP-19 and QQET-30) were identified in human plasma by HPLC-ESI-MS. The VGF C-terminus, the above two cleaved peptides, and the TLQP-21 related peptide/s were studied using ELISA and immunohistochemistry. In euglycemic patients, plasma NAPPE and TLQP like peptides were significantly reduced with obesity (74±10 vs. 167±28, and 92±10 vs. 191±19 pmol/ml, mean+SEM, n = 10 and 6, obese vs. normal BMI, respectively, p<0.03). Upon a standard glucose load, a distinct response was shown for VGF C-terminus, TLQP and QQET-like (ERVW immunoreactive) peptides in euglycemic normal BMI patients, but was virtually abolished in euglycemic obese, and in T2D patients independently of BMI. High-fat diet induced obese mice showed reduced plasma VGF C-terminus, NAPPE and QQET-like (ERVW) peptide/s (3±0.2 vs. 4.6±0.3, 22±3.5 vs. 34±1.3, and 48±7 vs. 100±7 pmol/ml, mean+SEM, n = 8/group, obese vs. slim, respectively, p<0.03), with a loss of the response to glucose for all VGF peptides studied. In immunohistochemistry, TLQP and/or VGF C-terminus antibodies labelled VGF containing perikarya in mouse celiac ganglia, pancreatic islet cells and thin beaded nerve fibres in brown adipose tissues, with fewer in white adipose tissue. Upon the glucose load, tyrosine hydroxylase and VGF C-terminus immunoreactive axons became apparent in pancreatic islets of slim animals, but not in obese animals. Alltogether, a significant loss of VGF peptide immunoreactivity and/or their response to glucose was demonstrated in obese patients, with or without T2D, in parallel with a similar loss in high-fat diet induced obese mice. An involvement of VGF in metabolic regulations, including those of brown and/or white adipose tissues is underlined, and may point out specific VGF peptides as potential targets for diagnosis and/or treatment.
Highlights
Type 2 diabetes (T2D) is a chronic disorder of carbohydrate, fat and protein metabolism, steadily increasing worldwide
Upon the oral glucose load, immunoreactivity for three out of four VGF peptides showed a significant response in euglycemic subjects, largely in the normal weight group (Fig 2, first two sets of bars: VGF C-terminus, TLQP and ERVW peptide/s)
Our study reports the novel identification of two VGF derived peptides in the human plasma, the distinct response of several VGF peptides to an oral glucose load (OGTT) in normal weight subjects, and their down regulation and blunted response in obese subjects and in T2D patients
Summary
Type 2 diabetes (T2D) is a chronic disorder of carbohydrate, fat and protein metabolism, steadily increasing worldwide. VGF mRNA is selectively expressed in neurons and neuroendocrine elements, and its primary translation product, the VGF protein, gives rise to several low molecular weight VGF peptides [10, 11]. These are stored in secretory vesicles and can be secreted upon stimuli [12, 13]. One such naturally occurring VGF peptide, TLQP-21, was shown to increase resting energy expenditure upon intracerebroventricular injection [14]. The number of neurons expressing both NPY and VGF was increased in the hypothalamic infundibular nucleus, but decreased in the nucleus of tractus solitarius of T2D patients, compared to non-diabetic controls [22]
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