Leptin targets in the brain regulating body weight : receptors and down-stream mediators of leptin in neurons of the hypothalamus and brainstem
Author: Håkansson Ovesjö, Marie-Louise
Date: 2000-06-15
Location: Samuelssonsalen, Scheelelaboratoriet, Tomtebodavägen 6
Time: 9.00
Department: Institutionen för neurovetenskap / Department of Neuroscience
Abstract
Abstract - Obesity is a disease which has become a global epidemic that
is beginning to replace undernutrition and infectious diseases as the
most significant contributor to ill health in the world. In particular,
obesity is associated with diabetes mellitus, hypertension and coronary
heart disease. The brain, primarily the hypothalamus, plays a fundamental
role in regulating body weight. During the last decade our knowledge on
the specific mediators and neuronal networks that regulate food intake
and body weight has increased dramatically. An important contribution to
the understanding of hypothalamic control of food intake has been the
characterization of the ob gene product (leptin) via positional cloning.
Leptin (from the Greek word leptos meaning thin) is a cytokine hormone
produced and secreted by adipose tissue, which acts via neuronal circuits
in the brain to reduce food intake and body weight. Absence of leptin as
seen in ob/ob mice results in obesity, diabetes and infertility. The
hormone leptin binds to and activates specific leptin receptors (Ob-R)
and regulates gene transcription via activation of the JAK-STAT signal
transduction pathway (JAK = Janus kinase; STAT = signal transducers and
activators of transcription). There are at least five different isoforms
of Ob-R, one of which has a long intracellular domain (Ob-Rb) and is
considered the most important for JAK-STAT signaling. The aim of this
thesis was to identify cellular targets for leptin in the brain and
thereby clarifying the central mechanisms by which leptin regulates body
weight. In situ hybridization showed widespread expression of Ob-R mRNA
in the brain. Particularly strong expression was demonstrated in the
choroid plexus, representing short Ob-R isoform mRNA, and the
hypothalamus, reflecting mainly Ob-Rb mRNA. Using direct
immunofluorescence histochemistry, Ob-R immunoreactivity was demonstrated
in ventromedial arcuate neurons containing neuropeptide Y (NPY),
agouti-related protein (AGRP) and [gamma]-aminobutyric acid (GABA), and
in ventrolateral arcuate neurons containing proopiomelanocortin (POMC)
and cocaine- and amphetamine-regulated transcript (CART), in
corticotropin-releasing hormone (CRH)-containing neurons of the
parvicellular part of the paraventricular nucleus, and in
melanin-concentrating hormone (MCH)- and hypocretin/orexin-containing
neurons of the lateral hypothalamic area, indicating that these neurons
are targets for circulating leptin. Transcription factor STAT3, an
intracellular leptin mediator in the hypothalamus, was demonstrated in
leptin receptor-containing NPY/AGRP/GABA- and POMC/CART-containing
neurons of the arcuate nucleus and in MCH and hypocretin/orexin neurons
of the lateral hypothalamic area, suggesting that leptin may exert direct
effects on these neurons. STAT3 mRNA and protein levels were
down-regulated in the arcuate nucleus of obese leptin-deficient ob/ob
mice as compared to lean control mice, indicating that STAT3 is an
important signal transducer for leptin's action in the hypothalamic
arcuate nucleus. The mRNA levels for the glutamic acid decarboxylase
(GAD) isoforms GAD65 and GAD67, and mRNA levels for the vesicular GABA
transporter (VGAT) were not altered in ob/ob mice, suggesting that
chronic leptin-deficiency does not result in altered transcription of
these genes. Serotonergic neurons of the dorsal raphe nucleus contain
Ob-R and Ob-Rb. Obese ob/ob mice have significantly lower levels of
serotonin transporter mRNA and display behavioral depression, suggesting
an altered serotonin neurotransmission in the absence of leptin and a
role for leptin in the regulation of serotonindependent brain functions.
Cholinergic neurons of the dorsal motor nucleus of the vagus nerve (DMX),
which innervate the stomach, contain Ob-R/Ob-Rb and STAT3. Leptin
inhibits gastric emptying when administered into the fourth ventricle,
indicating that leptin also acts via the brainstem to regulate food
intake and body weight.
List of papers:
I. Håkansson ML, Hulting AL, Meister B (1996). "Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus--relationship with NPY neurones" Neuroreport 7(18): 3087-3092
Pubmed
II. Håkansson ML, Brown H, Ghilardi N, Skoda RC, Meister B (1998). "Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus" J Neurosci 18(1): 559-572
Pubmed
III. Håkansson ML, Meister B (1998). "Transcription factor STAT3 in leptin target neurons of the rat hypothalamus" Neuroendocrinology 68(6): 420-427
Pubmed
IV. Håkansson ML, Collin M, Meister B (2000). "Down-regulated STAT3 messenger ribonucleic acid and STAT 3 protein in the hypothalamic arcuate nucleus of the obese leptin-deficient (ob/ob) mouse" Endocrinology (Submitted)
V. Håkansson-Ovesjö ML, Meister B (2000). "Leptin signaling and GABAergic neurons in the hypothalamic arcuate nucleus" (Manuscript)
VI. Håkansson M, de Lecea L, Sutcliffe JG, Yanagisawa M, Meister B. (1999). "Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus" J Neuroendocrinol 11(8): 653-663
Pubmed
VII. Collin M, Håkansson-Ovesjö ML, Misane I, Ögren SO, Meister B (2000). "Decreased 5-HT transporter mRNA in the dorsal raphe nucleus and behavioral depression in the obese leptin-deficient ob/ob mouse" Mol Brain Res (Submitted)
VIII. Smedh U, Håkansson ML, Meister B, Uvnäs-Moberg K (1998). "Leptin injected into the fourth ventricle inhibits gastric emptying" Neuroreport 9(2): 297-301
Pubmed
I. Håkansson ML, Hulting AL, Meister B (1996). "Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus--relationship with NPY neurones" Neuroreport 7(18): 3087-3092
Pubmed
II. Håkansson ML, Brown H, Ghilardi N, Skoda RC, Meister B (1998). "Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus" J Neurosci 18(1): 559-572
Pubmed
III. Håkansson ML, Meister B (1998). "Transcription factor STAT3 in leptin target neurons of the rat hypothalamus" Neuroendocrinology 68(6): 420-427
Pubmed
IV. Håkansson ML, Collin M, Meister B (2000). "Down-regulated STAT3 messenger ribonucleic acid and STAT 3 protein in the hypothalamic arcuate nucleus of the obese leptin-deficient (ob/ob) mouse" Endocrinology (Submitted)
V. Håkansson-Ovesjö ML, Meister B (2000). "Leptin signaling and GABAergic neurons in the hypothalamic arcuate nucleus" (Manuscript)
VI. Håkansson M, de Lecea L, Sutcliffe JG, Yanagisawa M, Meister B. (1999). "Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus" J Neuroendocrinol 11(8): 653-663
Pubmed
VII. Collin M, Håkansson-Ovesjö ML, Misane I, Ögren SO, Meister B (2000). "Decreased 5-HT transporter mRNA in the dorsal raphe nucleus and behavioral depression in the obese leptin-deficient ob/ob mouse" Mol Brain Res (Submitted)
VIII. Smedh U, Håkansson ML, Meister B, Uvnäs-Moberg K (1998). "Leptin injected into the fourth ventricle inhibits gastric emptying" Neuroreport 9(2): 297-301
Pubmed
Issue date: 2000-05-25
Publication year: 2000
ISBN: 91-628-4178-5
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