Leptin modulates fertility under the influence of elevated growth hormone as modeled in oMt1a-oGH transgenic mice

Abstract

Elevated growth hormone (GH) concentrations suppress reproductive function in a variety of species, although it is unclear whether GH directly suppresses reproductive performance, or whether GH activates other pathways to achieve these effects. The ovine metallothionein 1a-ovine GH (oMt1a-oGH) transgenic mouse has been used to model the effects of GH on both body composition and reproductive function. A recent report has documented increased leptin levels in obese oMt1a-oGH mice. Given the importance of leptin in modulation of the reproductive endocrine axis, as well as the reports documenting reduced leptin signal transduction in animals with elevated leptin levels, we hypothesized that high leptin concentrations in response to elevated GH would reduce fertility. To determine the effects of high circulating leptin levels on the reproductive endocrine axis, we assessed hypothalamic neuropeptide Y (NPY) and GnRH expression. At weaning, oMt1a-oGH transgenic (TG) and wild-type (WT) female mice were allocated to one of four treatment groups: oMt1a-oGH females chronically expressing the transgene (TG ON); oMt1a-oGH females expressing the transgene from 3 to 8 weeks of age (TG ON/OFF); WT females receiving the transgene stimulus from 3 to 8 weeks of age (WT ON/OFF); and WT females never receiving the transgene stimulus (WT OFF). Eight-week-old females were housed with males for a 2-week period, after which females were isolated from males and allowed to carry pregnancies to term. Body and gonadal fat pad (GFP) weights, along with plasma leptin concentrations, estrous cyclicity, pregnancy rate and litter characteristics, were recorded for each female. Chronic expression of the oMt1a-oGH transgene resulted in larger leaner mice, and inactivation of the transgene produced obese females. Pregnancy rate was reduced in TG ON females when compared with all other groups, and infertility was associated with elevated leptin levels. In addition, high leptin levels were associated with increased NPY expression, suggesting reduced leptin-signaling capacity, which may contribute to suppression of the reproductive axis in oGH animals.

Developmental programming: the role of growth hormone

“…Early dysregulation of GH promotes adipogenesis which in turn elevates leptin that influences adipose function at later ages. Elevated GH in a GH-transgenic mouse model increases plasma leptin [ 65 ] while mice transiently exposed to elevated GH during early postnatal development become obese having increased circulating leptin once the excess GH is withdrawn [ 54 ]. In these GH-transgenic mice, although each adipocyte expresses less leptin, the leptin in circulation is greater due to the increased overall adipocity.…”

“…This suggests that prolonged elevation of GH disrupts normal physiological responses to elevated plasma leptin, creating leptin resistance and obesity; in the case of elevated GH, the most likely site of leptin signaling impairment is at the hypothalamic axis. Supporting this view of GH generating leptin resistance is that the elevated GH in the GH- transgenic mouse increases plasma leptin as well as the leptin receptor (NPY) gene and protein expression [ 65 ]. It is proposed that leptin resistance can be programmed during fetal and neonatal life with long term impacts on body energy stores potentiating adult onset metabolic disorders [ 63 ].…”

Cysteine cathepsin S processes leptin, inactivating its biological activity

“…The role of leptin in energy homeostasis is demonstrated in the genetic obese mouse (Ob/Ob), which exhibits profound obesity, type II diabetes, and hyperphagia (Zhang et al 1994, Tartaglia 1997, Lago et al 2007. In addition to its important function in regulating food intake (Zhang et al 1994, Attele et al 2002, Sahu 2004, leptin is involved in several processes such as angiogenesis (Anagnostoulis et al 2008), blood pressure control (Haynes 2005), osteogenesis (Bertoni et al 2009), fertility (Thomas et al 2004), immune response, inflammation (Lago et al 2007), and atherosclerosis (Taleb et al 2007).…”