Περίληψη:
OBJECTIVE: This study examined the proteomic profile of the hypothalamus
in mice exposed to a high-fat diet (HFD) or with the anorexia of acute
illness. This comparison could provide insight on the effects of these
two opposite states of energy balance on appetite regulation.
METHODS: Four to six-week-old male C56BL/6J mice were fed a normal
(control 1 group; n = 7) or a HFD (HFD group; n = 10) for 8 weeks. The
control 2 (n = 7) and lipopolysaccharide (LPS) groups (n = 10) were fed
a normal diet for 8 weeks before receiving an injection of saline and
LPS, respectively. Hypothalamic regions were analysed using a
quantitative proteomics method based on a combination of techniques
including iTRAQ stable isotope labeling, orthogonal two-dimensional
liquid chromatography hyphenated with nanospray ionization and
high-resolution mass spectrometry. Key proteins were validated with
quantitative PCR.
RESULTS: Quantitative proteomics of the hypothalamous regions profiled a
total of 9249 protein groups (q < 0.05). Of these, 7718 protein groups
were profiled with a minimum of two unique peptides for each.
Hierachical clustering of the differentiated proteome revealed distinct
proteomic signatures for the hypothalamus under the HFD and LPS
nutritional conditions. Literature research with in silico
bioinformatics interpretation of the differentiated proteome identified
key biological relevant proteins and implicated pathways. Furthermore,
the study identified potential pharmacologic targets. In the LPS groups,
the anorexigen pro-opiomelanocortin was downregulated. In mice with
obesity, nuclear factor-kappa B, glycine receptor subunit alpha-4 (GlyR)
and neuropeptide Y levels were elevated, whereas serotonin receptor 1B
levels decreased.
CONCLUSIONS: High-precision quantitative proteomics revealed that under
acute systemic inflammation in the hypothalamus as a response to LPS,
homeostatic mechanisms mediating loss of appetite take effect.
Conversely, under chronic inflammation in the hypothalamus as a response
to HFD, mechanisms mediating a sustained `perpetual cycle' of appetite
enhancement were observed. The GlyR protein may constitute a novel
treatment target for the reduction of central orexigenic signals in
obesity.
Συγγραφείς:
Manousopoulou, A.
Koutmani, Y.
Karaliota, S.
Woelk, C. H.
and Manolakos, E. S.
Karalis, K.
Garbis, S. D.
