TLQP-21 A VGF-derived Peptide Prevents
Weight Gain and Adiposity
TLQP-21, a VGF-derived peptide, increases
energy expenditure and prevents the early phase of diet-induced
obesity
The vgf gene has been identified
as an energy homeostasis regulator. Vgf encodes
a 617-aa precursor protein that is processed to yield
an incompletely characterized panel of neuropeptides.
Until now, it was an unproved assumption that VGF-derived
peptides could regulate metabolism. Here, a VGF peptide
designated TLQP-21 was identified in rat brain extracts
by means of immunoprecipitation, microcapillary liquid
chromatography–tandem MS, and database searching
algorithms. Chronic intracerebroventricular (i.c.v.) injection
of TLQP-21 (15 µg/day for 14 days) increased resting
energy expenditure (EE) and rectal temperature in mice.
These effects were paralleled by increased epinephrine
and up-regulation of brown adipose tissue 2-AR
(2 adrenergic
receptor) and white adipose tissue (WAT) PPAR-
(peroxisome proliferator-activated receptor ),
3-AR, and UCP1
(uncoupling protein 1) mRNAs and were independent of locomotor
activity and thyroid hormones. Hypothalamic gene expression
of orexigenic and anorexigenic neuropeptides was unchanged.
Furthermore, in mice that were fed a high-fat diet for
14 days, TLQP-21 prevented the increase in body and WAT
weight as well as hormonal changes that are associated
with a high-fat regimen. Biochemical and molecular analyses
suggest that TLQP-21 exerts its effects by stimulating
autonomic activation of adrenal medulla and adipose tissues.
In conclusion, we present here the identification in the
CNS of a previously uncharacterized VGF-derived peptide
and prove that its chronic i.c.v. infusion effected an
increase in EE and limited the early phase of diet-induced
obesity.
Bartolomucci
A, et al. Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14584-9.
VGF is required for obesity induced by diet,
gold thioglucose treatment, and agouti and is differentially
regulated in pro-opiomelanocortin- and neuropeptide
Y-containing arcuate neurons in response to fasting Targeted deletion of the gene encoding the
neuronal and neuroendocrine secreted polypeptide VGF
(nonacronymic) produces a lean, hypermetabolic mouse.
Consistent with this phenotype, VGF mRNA levels are
regulated in the hypothalamic arcuate nucleus in response
to fasting. To gain insight into the site(s) and mechanism(s)
of action of VGF, we further characterized VGF expression
in the hypothalamus. Double-label studies indicated
that VGF and pro-opiomelanocortin were coexpressed in
lateral arcuate neurons in the fed state, and that VGF
expression was induced after fasting in medial arcuate
neurons that synthesize neuropeptide Y (NPY). Like NPY,
VGF mRNA induction in this region of the hypothalamus
in fasted mice was inhibited by exogenous leptin. In
leptin-deficient ob/ob and receptor-mutant db/db mice,
VGF mRNA levels in the medial arcuate were elevated.
To identify neural pathways that are functionally compromised
by Vgf ablation, VGF mutant mice were crossed with obese
A(y)/a (agouti) and ob/ob mice. VGF deficiency completely
blocked the development of obesity in A(y)/a mice, whereas
deletion of Vgf in ob/ob mice attenuated weight gain
but had no impact on adiposity. Hypothalamic levels
of NPY and agouti-related polypeptide mRNAs in both
double-mutant lines were dramatically elevated 10- to
15-fold above those of wild-type mice. VGF-deficient
mice were also found to resist diet- and gold thioglucose-induced
obesity. These data and the susceptibility of VGF mutant
mice to monosodium glutamate-induced obesity are consistent
with a role for VGF in outflow pathways, downstream
of hypothalamic and/or brainstem melanocortin 4 receptors,
that project via the autonomic nervous system to peripheral
metabolic tissues and regulate energy homeostasis.
Hahm S., et al. The Journal of
Neuroscience, August 15, 2002, 22(16):6929-6938
Schematic model indicating the sites where VGF may regulate
energy balance, based on genetic, histochemical, and lesion
data. Arcuate orexigenic and anorexigenic projections
are shown as gray and white, respectively.
Regions of the nervous system in which VGF mRNA or protein
is abundantly expressed and/or regulated by feeding or
GI manipulation are indicated by a speckled pattern.
The dashed lines identify areas susceptible to
GTG- or MSG-induced injury. Dark-gray projections
outlined in black, downstream of agouti
effects on the MC4-R, represent possible candidate circuits
that might be regulated by locally synthesized VGF (speckled
areas). ARC, Arcuate nucleus; DRG,
dorsal root ganglia; LH, lateral hypothalamus;
VMN, ventromedial nucleus. Hahm S., et al. The Journal
of Neuroscience, August 15, 2002, 22(16):6929-6938
VGF is required for the development of obesity in agouti
mice. Representative agouti (Ay/a)
and double-mutant (Vgf/Vgf,Ay/a)
mice are shown (A). Body weight (B)
and body composition (C) measurements for the
indicated genotypes are shown (mean ± SE).
Histograms identified by different letters are
significantly different from one another (B)
(p < 0.05; ANOVA with Tukey-Kramer
post hoc comparisons; n = number
of mice analyzed of the indicated genotype).
Hahm S., et al. The Journal
of Neuroscience, August 15, 2002, 22(16):6929-6938
VGF is required for the development of hyperphagia but
not increased adiposity in ob/ob mice. Representative
males of the following genotypes are shown: VGF mutant
(Vgf/Vgf),
double-mutant (Vgf/Vgf,ob/ob),
ob/ob, and wild type (A). Body weight
(B), body composition (C), and daily
food intake (D) were measured for the indicated
genotypes (mean ± SE). Histograms identified
by different letters are significantly different
from one another (B, D) (p < 0.05;
ANOVA with Tukey-Kramer post hoc comparisons;
n = number of mice analyzed of the
indicated genotype).
Hahm S., et al. The Journal of Neuroscience,
August 15, 2002, 22(16):6929-6938
2-AR
(
(peroxisome proliferator-activated receptor 
/Vgf
