title: Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge.
abstract: Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.
authors.affiliation: Avenida Bandeirantes, 3900, 14049-900, Ribeirao Preto, Sao Paulo, Brazil. llelias@fmrp.usp.br
authors.forename: Beatriz C
authors.initials: BC
authors.lastname: Borges
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Rorato
authors.forename: Yosefa
authors.initials: Y
authors.lastname: Avraham
authors.forename: Lilian E C M
authors.initials: LE
authors.lastname: da Silva
authors.forename: Margaret
authors.initials: M
authors.lastname: Castro
authors.forename: Lia
authors.initials: L
authors.lastname: Vorobiav
authors.forename: Elliot
authors.initials: E
authors.lastname: Berry
authors.forename: Jose
authors.initials: J
authors.lastname: Antunes-Rodrigues
authors.forename: Lucila L K
authors.initials: LL
authors.lastname: Elias
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids; D004731:Endotoxins / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D005989:Glycerides / Q000502:physiology; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D020738:Leptin / Q000097:blood / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D053701:Receptors, Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D054411:Receptors, Leptin / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001095:Arachidonic Acids; D004041:Dietary Fats; D063388:Endocannabinoids; D004731:Endotoxins; D005989:Glycerides; D020738:Leptin; D008070:Lipopolysaccharides; D044105:Receptor, Melanocortin, Type 4; D053701:Receptors, Interleukin-10; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; C094503:glyceryl 2-arachidonate; D017868:Cyclic AMP-Dependent Protein Kinases