The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity.

Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
Cell Metabolism (Impact Factor: 16.75). 02/2005; 1(1):63-72. DOI: 10.1016/j.cmet.2004.12.004
Source: PubMed

ABSTRACT Leptin is required for normal energy and glucose homeostasis. The hypothalamic arcuate nucleus (ARH) has been proposed as an important site of leptin action. To assess the physiological significance of leptin signaling in the ARH, we used mice homozygous for a FLPe-reactivatable, leptin receptor null allele (Lepr(neo/neo) mice). Similar to Lepr(db/db) mice, these mice are obese, hyperglycemic, hyperinsulinemic, infertile, and hypoactive. To selectively restore leptin signaling in the ARH, we generated an adeno-associated virus expressing FLPe-recombinase, which was delivered unilaterally into the hypothalamus using stereotaxic injections. We found that unilateral restoration of leptin signaling in the ARH of Lepr(neo/neo) mice leads to a modest decrease in body weight and food intake. In contrast, unilateral reactivation markedly improved hyperinsulinemia and normalized blood glucose levels and locomotor activity. These data demonstrate that leptin signaling in the ARH is sufficient for mediating leptin's effects on glucose homeostasis and locomotor activity.


Available from: Masumi Ichinose, Jun 02, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Elevations in brain angiotensin-II cause increased energy expenditure and a lean phenotype. Interestingly, the metabolic effects of increased brain angiotensin-II mimic the actions of leptin, suggesting an interaction between the two systems. Here we demonstrate that angiotensin-type 1a receptors (AT1aR) in the subfornical organ (SFO), a forebrain structure emerging as an integrative metabolic center, play a key role in the body weight-reducing effects of leptin via brown adipose tissue (BAT) thermogenesis. Cre/LoxP technology coupled with targeted viral delivery to the SFO in a mouse line bearing a conditional allele of the Agtr1a gene was utilized to determine the interaction between leptin and SFO AT1aR in metabolic regulation. Selective deletion of AT1aR in the SFO attenuated leptin-induced weight loss independent of changes in food intake or locomotor activity. This was associated with diminished leptin-induced increases in core body temperature, blunted upregulation of BAT thermogenic markers, and abolishment of leptin-mediated sympathetic activation to BAT. These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation.
    01/2015; 4(4). DOI:10.1016/j.molmet.2015.01.007
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leptin action in the brain has emerged as an important regulator of liver function independently from its effects on food intake and body weight. The autonomic nervous system plays a key role in the regulation of physiological processes by leptin. Here, we used direct recording of nerve activity from sympathetic or vagal nerves subserving the liver to investigate how brain action of leptin controls hepatic autonomic nerve activity. Intracerebroventricular (ICV) administration of leptin activated hepatic sympathetic traffic in rats and mice in dose- and receptor-dependent manners. The hepatic sympatho-excitatory effects of leptin were also observed when leptin was microinjected directly into the arcuate nucleus (ARC), but not into the ventromedial hypothalamus (VMH). Moreover, using pharmacological and genetic approaches, we show that leptin-induced increase in hepatic sympathetic outflow depends on PI3K but not AMP-activated protein kinase (AMPK), STAT3, or ERK1/2. Interestingly, ICV leptin also increased hepatic vagal nerve activity in rats. We show that this response is reproduced by intra-ARC, but not intra-VMH, leptin administration and requires PI3K and AMPK. We conclude that central leptin signaling conveys the information to the liver through the sympathetic and parasympathetic branches of the autonomic nervous system. Our data also provide important insight into the molecular events underlying leptin's control of hepatic autonomic nerve activity by implicating PI3K and AMPK pathways. Copyright © 2015 the authors 0270-6474/15/350474-11$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2015; 35(2):474-484. DOI:10.1523/jneurosci.1828-14.2015 · 6.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since its discovery in 1922, insulin has been thought to be required for normal metabolic homeostasis and survival. However, this view would need to be revised as recent results from different laboratories have convincingly indicated that life without insulin is possible in rodent models. These data indicate that particular neuronal circuitries, which include hypothalamic leptin-responsive neurons, are empowered with the capability of permitting life in complete absence of insulin. Here, we review the neuronal and peripheral mechanisms by which leptin signaling in the central nervous system (CNS) regulates glucose metabolism in an insulin-independent manner.
    Frontiers in Neuroscience 01/2015; 9:108. DOI:10.3389/fnins.2015.00108