title: Fibroblast growth factor 21 has no direct role in regulating fertility in female mice.
abstract: OBJECTIVE
  Reproduction is an energetically expensive process. Insufficient calorie reserves, signaled to the brain through peripheral signals such as leptin, suppress fertility. Recently, fibroblast growth factor 21 (FGF21) was implicated as a signal from the liver to the hypothalamus that directly inhibits the hypothalamic-gonadotropin axis during fasting and starvation. However, FGF21 itself increases metabolic rate and can induce weight loss, which suggests that the effects of FGF21 on fertility may not be direct and may reflect changes in energy balance.
  
  
  METHODS
  To address this important question, we evaluated fertility in several mouse models with elevated FGF21 levels including ketogenic diet fed mice, fasted mice, mice treated with exogenous FGF21 and transgenic mice over-expressing FGF21.
  
  
  RESULTS
  We find that ketogenic diet fed mice remain fertile despite significant elevation in serum FGF21 levels. Absence of FGF21 does not alter transient infertility induced by fasting. Centrally infused FGF21 does not suppress fertility despite its efficacy in inducing browning of inguinal white adipose tissue. Furthermore, a high fat diet (HFD) can restore fertility of female FGF21-overexpressing mice, a model of growth restriction, even in the presence of supraphysiological serum FGF21 levels.
  
  
  CONCLUSIONS
  We conclude that FGF21 is not a direct physiological regulator of fertility in mice. The infertility observed in FGF21 overexpressing mice is likely driven by the increased energy expenditure and consequent excess calorie requirements resulting from high FGF21 levels.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Garima
authors.initials: G
authors.lastname: Singhal
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Douris
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Fish
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Xinyao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Lilly Research Laboratories, Diabetes Research, Indianapolis, IN, 46225, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. Electronic address: ppissios@bidmc.harvard.edu.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Pissios
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. Electronic address: emaratos@bidmc.harvard.edu.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
keywords: FGF21; Fertility; Hypothalamic action; Leptin