Cell News 2/2016
21
DGZ AWARD WINNERS 2016
intraperitoneal (ip) injection of insulin and the excursion of blood
glucose levels is measured over time. We therefore performed ITT in
our models of acute activation of AgRP-neurons via chemogenetic
(i.e. ip CNO injection) or optogenetic (i.e. blue light turned on du-
ring the ITT). We found that in both cases, insulin led to a decrease
of blood glucose but the ability of insulin to decrease glucose levels
was lower in mice with chemogenetic (Figure 3C) and optogenetic
(Figure 3D) activation of AgRP-neurons (Steculorum et al., 2016).
These results revealed that acute activation of AgRP-neurons de-
creased systemic insulin sensitivity.
Investigations of which aspect of systemic glucose homeostasis is
affected upon acute activation of AgRP-neurons pinpointed a criti-
cal role for the brown adipose tissue (BAT), as revealed notably by a
decreased insulin-stimulated glucose uptake in BAT specifically. To
investigate further the role of BAT in AgRP-neurons-mediated in-
sulin resistance, we performed a gene expression analysis on BAT-
mRNA of control and ChR2AgRP-mice that had been photo-stimu-
lated in the ARH for one hour. Gene ontology enrichment analysis
revealed an overrepresentation of genes associated with myocyte
differentiation and muscle function, with notably a 18 fold incre-
ase of BAT myostatin upon acute AgRP-neurons activation (Figure
3E). This discovery was in line with the fact that BAT-precursor
cells originate from a Myf-5-positive lineage, which can give rise
either to myocytes or brown adipocytes. Interestingly, previous re-
ports already highlighted a role for myostatin in obesity and insulin
resistance (Bonala et al., 2014). We therefore decided to further
investigate its role in AgRP-mediated insulin resistance. Among
different experiments that we performed, we notably showed that
pre-treatment with a myostatin-blocking antibody (Ab) comple-
tely rescued the insulin resistance induced by acute activation of
AgRP-neurons, indicating that AgRP-neuron-dependent activation
of myostatin-expression significantly contributes to the manifes-
tation of systemic insulin resistance.
AgRP-neurons are known to project in several brain regions, and
the architecture of AgRP neurocircuits controlling feeding have
been unravelled recently (Betley et al., 2013). To investigate which
AgRP-projections are responsible for the acute glucose-regulatory
action of these neurons, we employed an optogenetic mapping
approach. For this purpose, we implanted optical fibers into AgRP-
neuron projection sites and compared the effect of stimulating
AgRP-fibers in specific projection sites on insulin sensitivity, as as-
sessed by ITT. These experiments pinpointed that the feeding and
insulin sensitivity are controlled by both distinct and overlapping
projections. We discovered that the insulin-sensitivity effects and
the modulation of BAT myostatin mRNA secondary to acute activa-
tion of AgRP-neurons are specifically mediated via the projection
of AgRP neurons to the ventro-lateral part of the bed nucleus of
the stria termialis (BNST_vl) (Figure 3F).
Thus, our work deciphered the basic architecture for the control
of peripheral insulin sensitivity controlled by AgRP-neurons. Coll-
ectively our results suggest that AgRP-neurons in mice induce not
only feeding, but also insulin resistance by stimulating expressi-
on of muscle-related genes in BAT, unravelling a mechanism by
which AgRP-neurons acutely coordinate hunger states with glu-
cose homeostasis.
Conclusions and outlook
Alarming predictive studies estimate that if the increasing trend
of obesity prevalence continues, more than half of the American
adults will be obese by 2030 (Wang et al., 2008), and this trend
may also hold true in European countries. Considering the heath
and economic burden of obesity, Type 2 Diabetes and associated di-
seases, there is an urge to define better therapeutical strategies. To
address the challenge of discovering new drugs and putative tar-
gets, we need to better understand the fundamental homeostatic
processes governing energy balance and glycemic control. In this
line, findings arising from our work may form the basis for novel
therapeutic options that could potentially modulate the function
of AgRP-neurocircuitry to tackle obesity associated hyperphagia
and insulin resistance. Importantly, while these data provide im-
petus to pursue antagonists for these pathways as novel targets for
the treatment of obesity and diabetes, further work is necessary to
delineate in depth the exact role of these new players.
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Carien Niessen, Sophie Steculorum, Dr. Michael Möller (Nikon GmbH)
