Somatostatin, a negative-regulator of central leptin action in the rat hypothalamus.
Leptin-responsive neurons of the hypothalamus constitute a heterogeneous population expressing a vast array of different neuropeptides and neurotransmitters, some of which participate in the regulation of hunger and satiety. Here we report that somatostatin modulates the efficacy of leptin-signalling in the rat hypothalamus. Using a two-pulse paradigm at 30-min intervals, we delivered somatostatin or somatostatin receptor subtype-selective agonists in combination with leptin into the lateral cerebral ventricle of stereotaxically cannulated rats. To monitor the effect of somatostatin on the leptin-signalling pathway, we quantified changes in the leptin-mediated activation of STAT3, the signal transducer and activator of transcription 3. Successive administration of somatostatin and leptin diminished the level of STAT3-phosphorylation and nuclear STAT3 translocation in the ventromedial and dorsomedial hypothalamic nuclei, the lateral hypothalamic area, and the arcuate nucleus by about 40% compared to leptin administration alone. Furthermore, application of subtype-selective somatostatin receptor agonists suggests that the observed reduction in leptin-responsiveness is predominantly mediated by the sst3 receptor-subtype, followed by sst1 and sst2. In addition, the intensity of the negative-regulatory effect of somatostatin on leptin-signalling displayed regional differences for the three receptor-subtypes involved. Addressing the functional consequences of the diminished leptin-signalling, behavioural analyses showed that centrally applied somatostatin counteracts the leptin-mediated suppression of food intake. These results suggest that the pleiotropic effector somatostatin also plays a role in the central regulation of energy homeostasis.
Stepanyan
Z
Z
Department of Molecular Genetics, German Institute of Human Nutrition Potsdam-Rehbrücke Nethetal, Germany.
Kocharyan
A
A
Behrens
M
M
Koebnick
C
C
Pyrski
M
M
Meyerhof
W
W
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D005455:Fluorescent Antibody Technique / Q000379:methods; D007031:Hypothalamus / Q000033:anatomy & histology / Q000187:drug effects*; D007276:Injections, Intraventricular / Q000379:methods; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013004:Somatostatin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000577:Amides; C429627:L796778; D020738:Leptin; D009578:Nitrobenzenes; D050796:STAT3 Transcription Factor; D013004:Somatostatin