Leptin Within the Subphysiological to Physiological Range Dose Dependently Improves Male Reproductive Function in an Obesity Mouse Model.
Obesity has recently been linked with reduced fertility, and the mechanisms underpinning this effect are currently unknown. The adipokine leptin is dysregulated in obesity and affects reproductive tracts; therefore, we investigated the dose-dependent effects of leptin on Leydig cell function and spermatogenesis. Eight-week-old leptin-deficient obese (ob/ob) male mice were treated with subphysiological (0.1- or 0.5-mg/kg body weight [BW]/d) or physiological (3.0-mg/kg BW/d) doses of leptin or saline for 12 weeks (chronic treatment) or 72 hours (acute treatment). We then evaluated male reproductive function markers. Mean testis weight increased significantly in the 0.1- and 3.0-mg/kg BW/d groups compared with saline controls (both P < .05). Intratesticular testosterone levels relative to testis weight significantly increased in the 0.5-mg/kg BW/d group compared with saline controls (P < .05). FSH levels increased in a dose-dependent manner with leptin treatment, whereas LH levels did not change. Leptin treatment significantly up-regulated both mRNA and protein expression of the steroidogenic enzyme cytochrome P450 17A1. Spermatogenesis improved in leptin-treated animals. Significantly more seminiferous tubules were observed in stages I-VIII (P < .01), and there were fewer abnormal seminiferous tubule structures (P < .01). Acute treatment with physiological leptin doses partially improved male reproductive markers without changing BW. Administration of subphysiological to physiological doses of leptin improves Leydig cell function and spermatogenesis.
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Annett
A
Hoffmann
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Gloria-Maria
GM
Manjowk
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Isabel Viola
IV
Wagner
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Nora
N
Klöting
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Thomas
T
Ebert
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Beate
B
Jessnitzer
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Ulrike
U
Lössner
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Jan-Bernd
JB
Stukenborg
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Matthias
M
Blüher
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Michael
M
Stumvoll
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Olle
O
Söder
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Konstantin
K
Svechnikov
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Mathias
M
Fasshauer
Department of Endocrinology and Nephrology (A.H., G.-M.M., T.E., B.J., U.L., M.B., M.S., M.F., S.K.), University of Leipzig, and Integrated Research and Treatment Center (IFB) Adiposity Diseases (I.V.W., N.K., T.E., U.L., M.F., S.K.), Leipzig University Medical Center, 04103 Leipzig, Germany; and Department of Women's and Children's Health, Pediatric Endocrinology Unit (I.V.W., J.-B.S., O.S., K.S.), Karolinska Institutet and University Hospital, 17176 Stockholm, Sweden.
Susan
S
Kralisch
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology*; D007985:Leydig Cells / Q000187:drug effects; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009929:Organ Size / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D012671:Seminiferous Tubules / Q000187:drug effects; D013091:Spermatogenesis / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013737:Testis / Q000187:drug effects*; D013739:Testosterone / Q000378:metabolism
D020738:Leptin; D013739:Testosterone; D005640:Follicle Stimulating Hormone; D013254:Steroid 17-alpha-Hydroxylase