Article

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.

0 Followers
 · 
96 Views
  • 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
  • [Show abstract] [Hide abstract]
    ABSTRACT: Leptin receptors (ObR) in the forebrain and hindbrain have been independently recognized as important mediators of leptin responses. We recently used low dose leptin infusions to show that chronic activation of both hypothalamic and hindbrain ObR is required to reduce body fat. The objective of this study was to identify the brain nuclei that are selectively activated in rats receiving chronic infusion of leptin in both the forebrain and the hindbrain. Either saline or leptin was infused into 3(rd) and 4(th) ventricles (0.1 µg/24h in 3(rd), 0.6 µg/24h in 4(th)) of male Sprague Dawley rats for 6 days using Alzet pumps. Rats infused with leptin into both ventricles (LL) showed a significant increase in pSTAT3 immunoreactivity (pSTAT3-ir) in the arcuate nucleus (Arc), ventromedial (VMH), dorsomedial (DMH) and posterior hypothalamus compared to other groups. No differences in pSTAT3-ir were observed in midbrain or hindbrain nuclei despite a 6 fold higher infusion of leptin into the 4(th) ventricle than the 3(rd). Delta Fos B-ir, a marker of chronic neuronal activation, showed that multiple brain nuclei were chronically activated due to the process of infusion, but only the Arc, VMH, DMH and ventral tuberomamillary nucleus showed a significant increase in LL rats compared to other groups. These data demonstrate that low dose leptin in the hindbrain increases pSTAT3 in areas of the hypothalamus known to respond to leptin, supporting the hypothesis that leptin induced weight loss requires an integrated response from both the hindbrain and forebrain. Copyright © 2014, American Journal of Physiology - Endocrinology and Metabolism.
    AJP Endocrinology and Metabolism 12/2014; DOI:10.1152/ajpendo.00501.2014 · 4.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Leptin alleviates hyperglycemia in rodent models of Type 1 diabetes by activating leptin receptors within the central nervous system. Here we delineate whether non-canonical leptin signaling through the Creb-regulated transcriptional coactivator 1 (Crtc1) contributes to leptin-dependent improvements in diabetic glucose metabolism. We employed mice with a targeted genetic disruption of Crtc1, tracer dilution techniques and neuroanatomical studies to interrogate whether Crtc1 enables leptin to improve glucose metabolism in streptozotocin-induced (STZ) diabetes. Here we show that leptin improves diabetic glucose metabolism through Crtc1-dependent and independent mechanisms. We find that leptin reduces diabetic hyperglycemia, hepatic gluconeogenic gene expression and selectively increases glucose disposal to brown adipose tissue and heart, in STZ-diabetic Crtc1 (WT) mice but not Crtc1 (+/-) mice. By contrast, leptin decreases circulating glucagon levels in both STZ-diabetic Crtc1 (WT) and Crtc1 (+/-) mice. We also demonstrate that leptin promotes Crtc1 nuclear translocation in pro-opiomelanocortin (Pomc) and non-Pomc neurons within the hypothalamic arcuate nucleus (ARC). Accordingly, leptin's ability to induce Pomc gene expression in the ARC is blunted in STZ-diabetic Crtc1 (+/-) mice. Our study reveals that Crtc1 functions as a conduit for leptin's glucoregulatory actions in insulin-dependent diabetes. This study also highlights a new role for Crtc1 in modulating peripheral glucose metabolism.
    12/2014; 4(3). DOI:10.1016/j.molmet.2014.12.006

Full-text (2 Sources)

Download
34 Downloads
Available from
May 31, 2014