Development of obesity following inactivation of a growth hormone transgene in mice

Abstract

Mice with a temporally regulatable ovine metallothionein 1a--ovine growth hormone transgene (oMT1a-oGH) were utilized to study the effects of withdrawal of elevated circulating levels of growth hormone (GH) on growth and body composition. The transgene was activated from 21-42 days of age by provision of zinc sulfate in the drinking water. At 42 days, mice were allocated to either activated transgenic (remain on zinc sulfate) or inactivated transgenic (removal of zinc sulfate) groups, and to receive either ad libitum or restricted (80-90% of ad libitum) access to feed. Non-transgenic control mice were treated similarly. Body weights and intakes were recorded weekly. Mice were killed at 70 d and epididymal and subcutaneous fat pads, trimmed hind carcass and various organs were weighed. The main findings of this study are: (1) food-restricted mice possessing an activated oMT1a-oGH transgene fail to demonstrate increased growth, but exhibit significantly reduced levels of fat (P < 0.05) relative to all other genotype x feed level combinations; and (2) inactivation of the oMT1a-oGH transgene, following a period of elevated GH levels, leads to development of obesity as evidenced by two to three fold increases in epididymal and subcutaneous fat pad weights (P < 0.01) relative to both activated transgenic and non-transgenic control mice. These large increases in fat deposition also occurred when intake was restricted to 80-90% of ad libitum levels, indicating that metabolic changes independent of intake occur in these inactivated transgenic mice. It is possible that highly elevated production of GH in activated oMT1a-oGH transgenic mice leads to (1) enhanced promotion of preadipocyte differentiation, leading to increased numbers of adipocytes that, upon cessation of oGH production, are available for lipid deposition resulting in obesity, or (2) alterations in production of or responsiveness to insulin, leading to increased fat deposition upon removal of the chronic anti-lipogenic actions of GH. The oMT1a-oGH transgenic mouse line should provide a new genetic model with which to investigate the mechanisms by which growth hormone affects obesity.

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

“…The lean phenotype of the TG ON mice is the result of improved feed efficiency and increased lean tissue deposition (Pomp et al 1992). The development of obesity in TG ON/OFF mice is also in agreement with previous work from our laboratory (Pomp et al 1996, Oberbauer et al 1997 1998). GH early in development, that is, beginning at 3 weeks of age, stimulates differentiation and proliferation of preadipocytes, resulting in more adipocytes in oMt1a-oGH than WT animals (Oberbauer et al 1997, Oberbauer & Murray 1998.…”

“…Expression of the oGH transgene results in a lean phenotype, while transgene inactivation promotes accrual of adipose tissue and eventual obesity (Pomp et al 1996, Oberbauer et al 1997, Oberbauer & Murray 1998. Oberbauer et al (2001) reported significantly higher circulating leptin concentrations in oGH females with an inactivated oGH transgene than in mice chronically overexpressing oGH.…”

Increased adiposity and insulin correlates with the progressive suppression of pulsatile GH secretion during weight gain

“…epididymal and subcutaneous fat mass, whereas a reversal of increased GH secretion results in a greater increase in epididymal fat mass relative to subcutaneous fat mass (Pomp et al 1996, Oberbauer et al 1997. Our data confirm that a decrease in GH secretion in mice occurs in parallel with an increase in epididymal fat mass.…”

The role of signal transducer and activator of transcription 5 in the inhibitory effects of GH on adipocyte differentiation

“…Growth hormone (GH) has been shown to play a critical role in regulating adipose tissue homeostasis in vivo (Donahue & Beamer 1993, Pomp et al 1996, Eisen et al 1998, Ikeda et al 1998, Lauterio et al 1998, Frick et al 2001. GH deficiency in humans is associated with obesity and increased adipocyte size and number, and treatment with GH restores adipose mass to normal levels (Salomon et al 1989, Johannsson et al 1997.…”