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Endocrinology 145(9):4022– 4024
Copyright © 2004 by The Endocrine Society
doi: 10.1210/en.2004-0861
Peripheral Signals Set the Tone for Central Regulation
of Metabolism
In 1849, Claude Bernard suggested that the central nervous
system (CNS) regulates blood glucose levels, after his classic
experiments showing that “piqûre” (pricking) of the floor of
the fourth ventricle of rabbits produced hyperglycemia (1).
Remarkably, he speculated that the effect was mediated by
stimulation of the sympathetic innervation of the liver. The
next major step was the work of Shimazu and colleagues (2),
who showed in 1965–1966, in line with these prescient observations, that glycogenolytic enzymes in the liver were
activated by splanchnic nerve stimulation and that specific
regions of the hypothalamus had reciprocal effects on blood
glucose levels and liver glycogen content (3). In this issue,
Perrin et al. (4) suggest a key role for the hypothalamus in
regulation of muscle glycogen synthesis through the autonomic nervous system (ANS).
Several regions of the brain are involved in regulation of
food intake and energy homeostasis. Among them, the hypothalamus is the most important locus involved in the neural control of peripheral metabolism through the modulation
of the ANS activity. The ANS indeed modulates hormone
secretion (i.e. insulin and glucagon secretion by pancreatic
islets) and metabolic activity of several tissues and organs
(i.e. liver, adipose tissue, and muscle). The hypothalamus is
in turn informed of the energy status of the organism by
several metabolic and hormonal signals, establishing a feed
back loop between the brain and the periphery (5) (Fig. 1).
According to the lipostatic model of the regulation of energy balance, peripheral signals proportional to the size of
energy stores communicate energy status to the brain. Leptin
and insulin are ideal candidates for this lipostatic function
because their levels are closely associated with adiposity, and
their central administration decreases food intake and increases energy expenditure (i.e. thermogenesis) (5).
Indeed, insulin and leptin receptors are expressed in several sites of the brain, including different hypothalamic nuclei such as, the ventromedial hypothalamus (VMH), the
lateral hypothalamic area, the paraventricular hypothalamus, the arcuate nucleus (ARH), and in the brainstem (6).
Leptin and insulin act mainly by modulating both the expression of neuropeptides (i.e. neuropeptide Y, agouti-related protein, proopiomelanocortin) in ARH and paraventricular hypothalamus and the neuronal electrical activity in
some hypothalamic nuclei (i.e. VMH and ARH), resulting in
modulation of ANS activity (6). Leptin stimulates fatty acid
oxidation and thermogenesis in brown adipose tissue
Abbreviations: AICAR, Pharmacological activator of AMPK; AMPK,
AMP-activated protein kinase; ANS, autonomic nervous system; ARH,
arcuate nucleus; CNS, central nervous system; ICV, intracerebroventricular; VMH, ventromedial hypothalamus.
Endocrinology is published monthly by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
through activation of sympathetic nerves (7). However, the
centrally mediated effect of insulin or leptin on peripheral
nonadipose tissue metabolism has been poorly studied until
recently. Indeed, we demonstrated that leptin injection stimulates fatty acid oxidation in muscle both directly and via the
hypothalamic sympathetic nervous system (8) (Fig. 1).
The hypothalamus-ANS axis also modulates glucose homeostasis in peripheral tissues via insulin-independent
mechanisms (9, 10). Acute administration of leptin either iv,
intracerebroventricular (ICV) (11), or intrahypothalamic
(into the VMH) (12, 13) increased glucose uptake in several
tissues including muscle, brown adipose tissue, and heart
through increased sympathetic nerve activity. Importantly,
the increase in glucose uptake despite unchanged insulin
levels indicated that leptin increases peripheral insulin sensitivity. Consistent with this hypothesis, administration of
leptin IV (14, 15) or ICV (16) during hyperinsulinemic euglycemic clamps markedly enhances insulin action on glucose uptake and utilization. Moreover, acute or chronic IV
administration of leptin alters hepatic glucose fluxes and
enhances insulin’s ability to inhibit hepatic glucose production (14, 17). Although little is known about the pathways
involved in the centrally mediated effects of leptin on peripheral insulin sensitivity, these effects are likely to involve
activation of central melanocortinergic neurons (18). Altogether, these data demonstrate that leptin acts in the CNS to
control glucose homeostasis in peripheral tissues as well as
peripheral insulin sensitivity.
Less is known regarding the central effect of insulin on
peripheral glucose homeostasis. Recent data from Rossetti’s
lab show that ICV insulin or a small-molecule insulin mimetic suppresses hepatic glucose production despite insulin
levels being clamped at basal circulating concentrations.
Moreover, antagonism of hypothalamic insulin signaling (i.e.
insulin receptor antisense, insulin receptor antibodies, or
pharmacologic inhibition of phosphoinositide 3-kinase) in
the presence of physiological hyperinsulinemia impaired the
ability of peripheral insulin to suppress glucose production
(19, 20). In these studies, peripheral glucose uptake was not
affected in the basal or hyperinsulinemic state by ICV insulin
or antagonism of hypothalamic insulin signaling, suggesting
that central insulin-mediated effects are specific to the liver.
However, data presented in this issue (4) show that ICV
administration of insulin markedly stimulates muscle glycogen synthesis at basal plasma insulin levels. Although, the
effects of central insulin were not investigated during hyperinsulinemic conditions, these data for the first time suggest that central insulin, like leptin, can also modulate muscle
glucose metabolism. The action of central insulin was mimicked by ICV administration of the pharmacological activator
of AMP-activated protein kinase (AMPK), AICAR. ICV
AICAR infusion increased both basal and insulin-stimulated
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Alquier and Kahn • News & Views
Endocrinology, September 2004, 145(9):4022– 4024 4023
FIG. 1. The hypothalamus is an important target of a number of key hormonal and metabolic signals. These signals integrate through neuronal
circuits to modulate the activity of the ANS, which regulates lipid and glucose metabolism as well as insulin sensitivity in peripheral tissues.
The hypothalamic-adrenal axis also plays a role (not shown). Recent findings indicate that hypothalamic AMPK is involved in these fuel sensing
mechanisms. Perrin et al. (4) show that insulin or AICAR injection into the brain acutely stimulates muscle glycogen synthesis whereas glucose
has opposite effects. These and other findings support the concept that the CNS not only regulates food intake and body weight, but also plays
a key role in regulating glucose homeostasis. *, AMPK-mediated pathways; LCFA, long chain fatty acids.
muscle glycogen synthesis, leading the authors to suggest
that brain AMPK could be involved in central insulin and/or
AICAR effects on peripheral insulin sensitivity. However,
the phosphorylation of hypothalamic AMPK was not modified after the 3 h of insulin or AICAR infusion, making
conclusions about the involvement of AMPK speculative.
Furthermore, ICV insulin has been shown to decrease hypothalamic AMPK activity (21).
Caution should also be exercised in ascribing an effect of
AICAR to AMPK activation. Indeed, AICAR also modulates
adenosine re-uptake in neurons, which leads to changes in
presynaptic glutamate release (excitatory neurotransmitter)
that could induce changes in peripheral metabolism independent of the AMPK effect (22). Interestingly, insulin-stimulated muscle glycogen synthesis is reduced in vivo in ␣2AMPK knockout mice, but this is likely to result from
elevated circulating catecholamines (23). Despite some discrepancies among these studies, the above metabolic data
indicate that elevation of brain insulin levels generates
changes in skeletal muscle metabolism aimed at facilitating
storage of energy as glycogen, as well as inhibiting liver
glucose production.
Leptin and insulin are not the only metabolic factors that
influence peripheral metabolism via central action (Fig. 1).
Indeed, fatty acids (24 –26) and glucose (4) can modulate not
only food intake but also peripheral insulin sensitivity. In-
terestingly, the paper in this issue (4) showed that ICV glucose infusion at high concentration markedly decreased insulin-stimulated muscle glycogen synthesis and inhibited
central effects of both insulin and AICAR, suggesting that
central glucose decreases insulin sensitivity. Whether the
hypothalamic pathways mediating these brain glucose effects involve hypothalamic AMPK is uncertain. AMPK has
been proposed to function as a fuel sensor in the hypothalamus (21, 26 –28), an evolutionarily conserved function of
this pathway that is important even in yeast (29). Although
high glucose has been shown to inhibit hypothalamic AMPK
activity (21, 26), in contrast to the study in this issue (4), high
glucose and insulin ICV had the same effect to suppress
AMPK activity (21). The demonstration of a role of cerebral
AMPK in the central effects of either AICAR, insulin, or
glucose on peripheral glucose metabolism in muscle, will
require molecular modulation of AMPK activity in the hypothalamus (dominant-negative, constitutively active
AMPK, neuronal specific knockout, etc.).
Although some discrepancies remain among studies, possibly related to differences in technical procedures or strain
of animals, these data indicate that hormonal and metabolic
signals play a key role not only in the control of energy intake
but also in peripheral glucose metabolism in muscle and liver
through the ANS. The precise neurocircuitry and the molecular factor(s) that integrate these signals and mediate
4024
Endocrinology, September 2004, 145(9):4022– 4024
these effects need to be clearly defined. Such studies are
likely to provide important clues to the links between obesity
and type 2 diabetes. The “treasure chest” could contain novel
therapeutic approaches to prevent or ameliorate obesity and
diabetes.
Thierry Alquier and Barbara B. Kahn
Division of Endocrinology, Diabetes and Metabolism
Beth Israel Deaconess Medical Center
and
Department of Medicine
Harvard Medical School
Boston, Massachusetts 02215
Alquier and Kahn • News & Views
12.
13.
14.
15.
16.
Acknowledgments
17.
We thank Y. Minokoshi and L. Rossetti for comments on the
manuscript.
18.
Received July 6, 2004. Accepted July 7, 2004.
Address all correspondence and requests for reprints to: Barbara B.
Kahn, M.D, Endocrine Division-Research North 325E, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Boston, Massachusetts
02215. E-mail: [email protected].
Work in the lab of B.B.K. was supported by National Institutes of
Health Grants R01 DK43051 and R01 DK56116. T.A. was supported by
an American Diabetes Association-European Association for the Study
of Diabetes fellowship and a Bettencourt-Schueller Foundation award.
19.
20.
21.
22.
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Endocrinology is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.