Molecular and neural mechanisms of leptin action: Focus on Reproduction

Transcription

1 Molecular and neural mechanisms of leptin action: Focus on Reproduction Martin G. Myers, Jr., M.D., Ph.D. and collaborators Division of Metabolism, Endocrinology and Diabetes Department of Internal Medicine University of Michigan Medical School Ann Arbor, MI

2 Odds Ratio for Infertility normal Rich-Edwards et al. (2002) Epidemiology 13: Body Mass Index (kg/m2)

3 Control of Physiology by the ob Gene Product, Leptin, and the db Gene Product, the Long () Isoform of the Leptin Receptor Reproduction Growth (GH, IGF-1) Metabolic Rate: Thyroid SNS tone Brain - Leptin Resistance appetite Glycemic control LEPTIN Adipocyte + Immune Function (T cell)

4 Disruption of physiology in ob/ob mice (lacking leptin) and db/db mice (lacking ) Infertile Decreased growth Low Metabolic Rate: Dec. Thyroid Dec. ANS tone Brain X + inc. appetite Type 2 Diabetes X LEPTIN - Dec. Immune Function Adipocyte

5 Main themes for the Myers Lab: 1. Molecular Mechanisms of Leptin Signaling and action

6 Main themes for the Myers Lab: 1. Molecular Mechanisms of Leptin Signaling and action 2. Neural Mechanisms of Leptin Action

7 Themes: 1. Molecular Mechanisms of Leptin Signaling and action 2. Neural Mechanisms of Leptin Action So where does leptin act? Leptin and Reproduction

8 Distribution of EGFP neurons in -EGFP mice 6000 PMv 3V Number of EGFP neurons V F ARC POA PVN VMH DMH ARH PMV LHA VTA RLi DR PAG PBN NTS

9 Neural mechanisms by which leptin could regulate the neuroendocrine reproductive axis?location LEPTIN ARC Kiss1 AVPV Kiss1 PMv GnRH LH secretion, Reproduction

10 Neural mechanisms by which leptin might regulate the neuroendocrine reproductive axis II: Indirect Action Where are the neurons??location LEPTIN ARC Kiss1 AVPV Kiss1 PMv GnRH LH secretion, Reproduction

11 Neural mechanisms by which leptin might regulate the neuroendocrine reproductive axis II: Indirect Action Where are the neurons??location LEPTIN ARC Kiss1 AVPV Kiss1 X PMv GnRH LH secretion, Reproduction

12 PMv cells express Neuronal Nitric Oxide Synthase (Nos1) -EGFP Nos1 merge

13 Inactivation of in PMv Nos1 Neurons to discern their role in leptin action ATG Stop Nos1 Cre Nos1 Exon 1 Final Exon IRES-cre pa loxp loxp fl/fl Exon 16 Exon Exon 18 Cre-mediated Recombination only in neurons coexpressing and Nts Inactivation in Nos1 Neurons loxp Exon 16 Exon 18 Nos1 -KO

14 Females

15 Pair Feeding

16 Pair Fed Ad Libitum Fed Vaginal Opening Vaginal Cornification Pair Fed Ad Libitum Fed

17 First Vaginal Estrus (VE1) Ad Libitum Fed Pair Fed

18 Onset of Vaginal Cycling (to d56) Ad Libitum Fed Pair Fed

19 Neural mechanisms by which leptin might regulate the neuroendocrine reproductive axis II: Indirect Action Where are the neurons??location Puberty onset? LEPTIN ARC Kiss1 AVPV Kiss1 PMv Cycling GnRH Anorexia

20 Neural mechanisms by which leptin might regulate the neuroendocrine reproductive axis II: Indirect Action Where are the neurons??location LEPTIN ARC Kiss1?? AVPV Kiss1? PMv GnRH How do PMv cells effect? Anorexia LH secretion, Reproduction

21 Collaborators MYERS LAB Gina Leinninger Mike Rajala Rebecca Leshan Eneida Villanueva Gwen Louis Scott Robertson Darren Opland Christa Patterson Justin Jones ZZ Zhang Miro Faouzi Natinder Saini Josh Skorupski Megan Greenwald-Yarnell Heike Münzberg (now PBRC) Funding: NIH, AHA, ADA, Marilyn Vincent Foundation OTHERS Peter Mancuso Streamson Chua Young-Hwan Jo Tamas Horvath Sabrina Diano Ed Feener Jarrod Marto Chris Rhodes Mike Schwartz Mark Sleeman Christian Bjørbaek Bob Thompson Audrey Seasholtz Diane Fingar Morris White Bob Kennedy/Maura Perry Jill Becker/Hongyan Yang Peter Mombaerts