Leptin-Mediated Hypothalamic Pathway of Cholecystokinin (CCK-8) to Regulate Body Weight in Free-Feeding Rats

• Published in: Endocrinology (Philadelphia) 2008-04, Vol.149 (4), p.1994-2000
• Main Authors: Merino, Beatriz, Cano, Victoria, Guzmán, Rocío, Somoza, Beatriz, Ruiz-Gayo, Mariano
• Format: Article
• Language: English
• Subjects: Acetyl-CoA Carboxylase - metabolism; Adipose tissue; Adipose Tissue - drug effects; Adiposity; AMP-activated protein kinase; AMP-Activated Protein Kinases; Animals; Arcuate nucleus; Biological and medical sciences; Body weight; Body Weight - drug effects; Cerebrospinal fluid; Cholecystokinin; Eating - drug effects; Energy balance; Food intake; Fundamental and applied biological sciences. Psychology; Hypothalamus; Hypothalamus - physiology; Kinases; Leptin - cerebrospinal fluid; Leptin - physiology; Leptin receptors; Male; Multienzyme Complexes - metabolism; Muscle, Skeletal - enzymology; Muscles; Musculoskeletal system; Peripheral circulation; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-fos - analysis; Rats; Rats, Sprague-Dawley; Signal transduction; Sincalide - pharmacology; Skeletal muscle; STAT3 Transcription Factor - analysis; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-1286

Regulation of body weight (BW) results from the interplay between different hormonal systems acting at central and peripheral level. This study aims at characterizing the involvement of cholecystokinin (CCK) in BW and energy balance regulation. We have characterized, in free-feeding rats, the effect of CCK-8 on 1) food intake, BW, and adiposity; 2) skeletal muscle metabolism; 3) leptin signaling pathway within the arcuate nucleus of the hypothalamus; and 4) the permeability of brain barriers to leptin. We demonstrate here that CCK-8 acutely decreases BW by a mechanism partially dependent on central leptin pathways, based on the following results: 1) the effect of CCK was less intense in rats lacking functional leptin receptors (Zucker fa/fa), 2) CCK-8 facilitated the uptake of leptin from peripheral circulation to cerebrospinal fluid (CSF), 3) the concentration of leptin in CSF of rats receiving CCK was more elevated in those animals showing higher loss of BW, and 4) CCK activated leptin signaling pathways within the hypothalamus as well as phosphorylation of AMP-activated protein kinase in skeletal muscle. We also suggest that gain of BW may be linked to individual susceptibility to the effect of CCK, because we observed that in animals treated with this hormone, the increase of BW negatively correlated with leptin concentration within the CSF. Our data show that CCK has a negative impact on energy balance and suggest that CCK facilitates the access of leptin to hypothalamic areas, thus allowing leptin to act on hypothalamic targets involved in BW control.