Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2015-03, Vol.17 (3), p.285-293
• Main Authors: Kanoski, S. E., Ong, Z. Y., Fortin, S. M., Schlessinger, E. S., Grill, H. J.
• Format: Article
• Language: English
• Subjects: Animals; Antidiabetics; Appetite Depressants - pharmacology; Body Weight - drug effects; Drug Therapy, Combination - methods; Eating - drug effects; exendin-4; Food; Food additives; Food intake; GLP-1; GLP-1 receptor agonists; Glucagon; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - pharmacology; Hypothalamus; Hypothalamus - drug effects; Incretins - pharmacology; Intracellular; Intracellular signalling; Leptin - pharmacology; Liraglutide; Male; Molecular modelling; obesity; Obesity - drug therapy; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - drug effects; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein-tyrosine-phosphatase; rat; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor - drug effects; synergy; Ventricle; Ventricles (cerebral); Weight; Weight Loss
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12423

Aim To investigate the behavioural and intracellular mechanisms by which the glucagon like peptide‐1 (GLP‐1) receptor agonist, liraglutide, and leptin in combination enhance the food intake inhibitory and weight loss effects of either treatment alone. Methods We examined the effects of liraglutide (a long‐acting GLP‐1 analogue) and leptin co‐treatment, delivered in low or moderate doses subcutaneously (s.c.) or to the third ventricle, respectively, on cumulative intake, meal patterns and hypothalamic expression of intracellular signalling proteins [phosphorylated signal transducer and activator of transcription‐3 (pSTAT3) and protein tyrosine phosphatase‐1B (PTP1B)] in lean rats. Results A low‐dose combination of liraglutide (25 µg/kg) and leptin (0.75 µg) additively reduced cumulative food intake and body weight, a result mediated predominantly through a significant reduction in meal frequency that was not present with either drug alone. Liraglutide treatment alone also reduced meal size; an effect not enhanced with leptin co‐administration. Moderate doses of liraglutide (75 µg/kg) and leptin (4 µg), examined separately, each reduced meal frequency, cumulative food intake and body weight; only liraglutide reduced meal size. In combination these doses did not further enhance the anorexigenic effects of either treatment alone. Ex vivo immunoblot analysis showed elevated pSTAT3 in the hypothalamic tissue after liraglutide‐leptin co‐treatment, an effect which was greater than that of leptin treatment alone. In addition, s.c. liraglutide reduced the expression of PTP1B (a negative regulator of leptin receptor signalling), revealing a potential mechanism for the enhanced pSTAT3 response after liraglutide‐leptin co‐administration. Conclusions Collectively, these results show novel behavioural and molecular mechanisms underlying the additive reduction in food intake and body weight after liraglutide‐leptin combination treatment.