Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance.
Hypoglycemia initiates the counter-regulatory response (CRR), in which the sympathetic nervous system, glucagon and glucocorticoids restore glucose to appropriate concentrations. During starvation, low leptin levels restrain energy utilization, enhancing long-term survival. To ensure short-term survival during hypoglycemia in fasted animals, the CRR must overcome this energy-sparing program and nutrient depletion. Here we identify in mice a previously unrecognized role for leptin and a population of leptin-regulated neurons that modulate the CRR to meet these challenges. Hypoglycemia activates neurons of the parabrachial nucleus (PBN) that coexpress leptin receptor (LepRb) and cholecystokinin (CCK) (PBN LepRb(CCK) neurons), which project to the ventromedial hypothalamic nucleus. Leptin inhibits these cells, and Cck(cre)-mediated ablation of LepRb enhances the CRR. Inhibition of PBN LepRb cells blunts the CRR, whereas their activation mimics the CRR in a CCK-dependent manner. PBN LepRb(CCK) neurons are a crucial component of the CRR system and may be a therapeutic target in hypoglycemia.
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Jonathan N
JN
Flak
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Christa M
CM
Patterson
Center for Integrative Physiology, University of Edinburgh, Edinburgh, UK.
Alastair S
AS
Garfield
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, and Department of Pharmacology, University of Cambridge, Cambridge, UK.
Giuseppe
G
D'Agostino
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Paulette B
PB
Goforth
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Ames K
AK
Sutton Hickey
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Paige A
PA
Malec
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Jenny-Marie T
JT
Wong
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Mark
M
Germani
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Justin C
JC
Jones
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Michael
M
Rajala
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Leslie
L
Satin
Kovler Diabetes Center, University of Chicago, Chicago, IL, USA.
Christopher J
CJ
Rhodes
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI, USA.
David P
DP
Olson
Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Robert T
RT
Kennedy
Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, and Department of Pharmacology, University of Cambridge, Cambridge, UK.
Lora K
LK
Heisler
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.|Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Martin G
MG
Myers
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D005260:Female; D007003:Hypoglycemia / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D065823:Parabrachial Nucleus / Q000187:drug effects / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism
D001786:Blood Glucose; D020738:Leptin; D054411:Receptors, Leptin; C515447:leptin receptor, mouse