Journal
CELL METABOLISM
Volume 18, Issue 3, Pages 431-444Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2013.08.004
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Funding
- Juvenile Diabetes Research Foundation [3-2011-405]
- American Heart Association
- National Science Foundation [NSFIIS-0513376]
- National Institutes of Health [FDK092083A, F32 DK078478, R01 DK089044, R01 DK075632, P30 DK046200, P30DK057521, RL1 DK081185, R37 DK053301, LM010235, NLM T15LM07443, R01 DK080836, R01 DK091680]
- Louis-Jeantet Foundation
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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 g-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.
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