title: Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin.
abstract: The dogma that life without insulin is incompatible has recently been challenged by results showing the viability of insulin-deficient rodents undergoing leptin monotherapy. Yet, the mechanisms underlying these actions of leptin are unknown. Here, the metabolic outcomes of intracerebroventricular (i.c.v.) administration of leptin in mice devoid of insulin and lacking or re-expressing leptin receptors (LEPRs) only in selected neuronal groups were assessed. Our results demonstrate that concomitant re-expression of LEPRs only in hypothalamic γ-aminobutyric acid (GABA) and pro-opiomelanocortin (POMC) neurons is sufficient to fully mediate the lifesaving and antidiabetic actions of leptin in insulin deficiency. Our analyses indicate that enhanced glucose uptake by brown adipose tissue and soleus muscle, as well as improved hepatic metabolism, underlies these effects of leptin. Collectively, our data elucidate a hypothalamic-dependent pathway enabling life without insulin and hence pave the way for developing better treatments for diseases of insulin deficiency.
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujikawa
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.forename: Vishal R
authors.initials: VR
authors.lastname: Patel
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ramadori
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Vianna
authors.forename: Linh
authors.initials: L
authors.lastname: Vong
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Thorel
authors.forename: Simona
authors.initials: S
authors.lastname: Chera
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Pierre
authors.initials: P
authors.lastname: Baldi
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppari
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000032:analysis; D006943:Hyperglycemia / Q000188:drug therapy / Q000401:mortality; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D020738:Leptin / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; D005947:Glucose