Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility.
Leptin-deficient (Lep(ob/ob)) mice are obese, diabetic, and infertile. Ablation of neurons that make agouti-related protein (AgRP) in moderately obese adult Lep(ob/ob) mice caused severe anorexia. The mice stopped eating for 2 wk and then gradually recovered. Their body weight fell to within a normal range for WT mice, at which point food intake and glucose tolerance were restored to that of WT mice. Remarkably, both male and female Lep(ob/ob) mice became fertile. Ablation of neurons that express melanin-concentrating hormone (MCH) in adult Lep(ob/ob) mice had no effect on food intake, body weight, or fertility, but resulted in improved glucose tolerance. We conclude that AgRP-expressing neurons play a critical role in mediating the metabolic syndrome and infertility of Lep(ob/ob) mice, whereas MCH-expressing neurons have only a minor role.
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Qi
Q
Wu
Benjamin B
BB
Whiddon
Richard D
RD
Palmiter
D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology; D005298:Fertility / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007028:Hypothalamic Hormones / Q000378:metabolism*; D020738:Leptin / Q000172:deficiency* / Q000378:metabolism; D008543:Melanins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010907:Pituitary Hormones / Q000378:metabolism*; D016019:Survival Analysis
D054369:Agouti-Related Protein; D007028:Hypothalamic Hormones; D020738:Leptin; D008543:Melanins; D010907:Pituitary Hormones; C019463:melanin-concentrating hormone; D005947:Glucose