title: Free fatty acids induce Lhb mRNA but suppress Fshb mRNA in pituitary LβT2 gonadotropes and diet-induced obesity reduces FSH levels in male mice and disrupts the proestrous LH/FSH surge in female mice.
abstract: Female obesity is associated with insulin resistance, hyperandrogenemia, and reproductive dysfunction. We hypothesized that elevated free fatty acids (FFAs) might directly modulate pituitary gonadotropin production. FFAs caused a time- and dose-dependent increase in phosphorylation of the MAPKs p38MAPK, c-Jun N-terminal kinase (JNK)-1/2, and ERK1/2 in LβT2 gonadotrope cells. Furthermore, FFAs up-regulated Lhb mRNA expression acutely, an effect that was blocked by JNK inhibition, but suppressed Fshb mRNA expression, an effect that was independent of MAPK signaling. FFAs enhanced the activation of the MAPKs in the presence of GnRH, although the cotreatment did not alter Lhb induction but did eliminate the GnRH induction of Fshb. FFAs also suppressed activin-induced Fshb expression. Knockdown experiments showed that the FFA effect on the inflammatory kinases p38MAPK and JNK and on Lhb, but not Fshb, mRNA expression is mediated via toll-like receptor-2 and toll-like receptor-4 and was mimicked by lipopolysaccharide stimulation. In vivo, male C57BL/6 mice on a high-fat diet showed reduced FSH levels consistent with the suppression of Fshb seen in vitro. Histological analysis of the testes showed an increased number of abnormal seminiferous tubules. Female mice on a high-fat diet lacked the expected proestrus LH and FSH surge and exhibited an increase in the number of days at estrus and a reduced number of days at proestrus, and ovaries had significantly fewer corpora lutea. Taken together, our findings suggest that lipid excess can lead to reproductive defects in both male and female mice.
authors.affiliation: Medical Research Service, Veterans Affairs San Diego Healthcare System, San Diego California 92161, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Morinaga
authors.forename: Vicky
authors.initials: V
authors.lastname: Hwang
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Fan
authors.forename: Marina O
authors.initials: MO
authors.lastname: Fernandez
authors.forename: Nissi
authors.initials: N
authors.lastname: Varki
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D037201:Follicle Stimulating Hormone, beta Subunit / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D052681:Gonadotrophs / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D037101:Luteinizing Hormone, beta Subunit / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D010902:Pituitary Gland / Q000166:cytology; D011359:Proestrus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D037201:Follicle Stimulating Hormone, beta Subunit; D037101:Luteinizing Hormone, beta Subunit; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases