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.
Subject(s)
Hypothalamus/drug effects , Insulin/metabolism , Leptin/pharmacology , Neurons/drug effects , Adipose Tissue, Brown/metabolism , Animals , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , GABAergic Neurons/drug effects , GABAergic Neurons/metabolism , Glucose/analysis , Hyperglycemia/drug therapy , Hyperglycemia/mortality , Hypothalamus/metabolism , Kaplan-Meier Estimate , Leptin/therapeutic use , Liver/metabolism , Mice , Muscle, Skeletal/metabolism , Neurons/metabolism , Receptors, Leptin/genetics , Receptors, Leptin/metabolismABSTRACT
Blood glucose levels are tightly controlled, a process thought to be orchestrated primarily by peripheral mechanisms (insulin secretion by ß cells, and insulin action on muscle, fat, and liver). The brain also plays an important, albeit less well-defined role. Subsets of neurons in the brain are excited by glucose; in many cases this involves ATP-mediated closure of K(ATP) channels. To understand the relevance of this, we are manipulating glucose sensing within glucose-excited neurons. In the present study, we demonstrate that glucose excitation of MCH-expressing neurons in the lateral hypothalamus is mediated by K(ATP) channels and is negatively regulated by UCP2 (a mitochondrial protein that reduces ATP production), and that glucose sensing by MCH neurons plays an important role in regulating glucose homeostasis. Combined, the glucose-excited neurons are likely to play key, previously unexpected roles in regulating blood glucose.