Insulin causes hyperthermia by direct inhibition of warm-sensitive neurons.
OBJECTIVE
Temperature and nutrient homeostasis are two interdependent components of energy balance regulated by distinct sets of hypothalamic neurons. The objective is to examine the role of the metabolic signal insulin in the control of core body temperature (CBT).


METHODS
The effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio. In vivo 2-[(18)F]fluoro-2-deoxyglucose uptake into brown adipose tissue (BAT) was measured in rats after insulin treatment by positron emission tomography combined with X-ray computed tomography imaging. Insulin receptor-positive neurons were identified by retrograde tracing from the raphe pallidus. Insulin was locally applied on hypothalamic slices to determine the direct effects of insulin on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates.


RESULTS
Injection of insulin into the preoptic area of the hypothalamus induced a specific and dose-dependent elevation of CBT mediated by stimulation of BAT thermogenesis as shown by imaging and respiratory ratio measurements. Retrograde tracing indicates that insulin receptor-expressing warm-sensitive neurons activate BAT through projection via the raphe pallidus. Insulin applied on hypothalamic slices acted directly on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. The hyperthermic effects of insulin were blocked by pretreatment with antibodies to insulin or with a phosphatidylinositol 3-kinase inhibitor.


CONCLUSIONS
Our findings demonstrate that insulin can directly modulate hypothalamic neurons that regulate thermogenesis and CBT and indicate that insulin plays an important role in coupling metabolism and thermoregulation at the level of anterior hypothalamus.
The Harold L. Dorris Neurological Research Institute, Department of Molecular and Integrative Neurosciences, The Scripps Research Institute, La Jolla, California, USA.
Manuel
M
Sanchez-Alavez
Iustin V
IV
Tabarean
Olivia
O
Osborn
Kayo
K
Mitsukawa
Jean
J
Schaefer
Jeffrey
J
Dubins
Kristina H
KH
Holmberg
Izabella
I
Klein
Joe
J
Klaus
Luis F
LF
Gomez
Hartmuth
H
Kolb
James
J
Secrest
Jeanine
J
Jochems
Kevin
K
Myashiro
Peter
P
Buckley
John R
JR
Hadcock
James
J
Eberwine
Bruno
B
Conti
Tamas
T
Bartfai
D002001:Adipose Tissue, Brown / Q000502:physiology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology*; D006979:Hyperthermia, Induced / Q000379:methods*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D007267:Injections; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology*; D011301:Preoptic Area / Q000187:drug effects / Q000502:physiology; D013686:Telemetry
D007328:Insulin