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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.<\/jats:p>","DOI":"10.1210\/en.2012-2218","type":"journal-article","created":{"date-parts":[[2013,3,23]],"date-time":"2013-03-23T04:27:59Z","timestamp":1364012879000},"page":"2188-2199","source":"Crossref","is-referenced-by-count":40,"title":["Free Fatty Acids Induce Lhb mRNA but Suppress Fshb mRNA in Pituitary L\u03b2T2 Gonadotropes and Diet-Induced Obesity Reduces FSH Levels in Male Mice and Disrupts the Proestrous LH\/FSH Surge in Female Mice"],"prefix":"10.1210","volume":"154","author":[{"given":"Shweta","family":"Sharma","sequence":"first","affiliation":[{"name":"Medical Research Service (S.S., V.H., M.O.F., N.J.G.W.), Veterans Affairs San Diego Healthcare System, San Diego California 92161"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Morinaga","sequence":"first","affiliation":[{"name":"the Departments of Medicine (S.S., H.M., V.H., W.F., M.O.F., J.M.O., N.J.G.W.), University of California, San Diego, San Diego, California 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicky","family":"Hwang","sequence":"first","affiliation":[{"name":"the Departments of Medicine (S.S., H.M., V.H., W.F., M.O.F., J.M.O., N.J.G.W.), University of California, San Diego, San Diego, California 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WuQiang","family":"Fan","sequence":"first","affiliation":[{"name":"the Departments of Medicine (S.S., H.M., V.H., W.F., M.O.F., J.M.O., N.J.G.W.), University of California, San Diego, San Diego, California 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina O.","family":"Fernandez","sequence":"first","affiliation":[{"name":"Medical Research Service (S.S., V.H., M.O.F., N.J.G.W.), Veterans Affairs San Diego Healthcare System, San Diego California 92161"},{"name":"the Departments of Medicine (S.S., H.M., V.H., W.F., M.O.F., J.M.O., N.J.G.W.), University of California, San Diego, San Diego, California 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nissi","family":"Varki","sequence":"first","affiliation":[{"name":"Pathology (N.V.), University of California, San Diego, San Diego, California 92093"},{"name":"the UCSD Cancer Center (N.V., N.J.G.W.), University of California, San Diego, San Diego, California 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerrold M.","family":"Olefsky","sequence":"first","affiliation":[{"name":"the Departments of Medicine (S.S., H.M., V.H., W.F., M.O.F., J.M.O., N.J.G.W.), University of California, San Diego, San Diego, California 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J. 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