Fasting-induced changes in the hypothalamic-pituitary-GH axis in the absence of GH expression: lessons from the spontaneous dwarf rat

Abstract

Fasting results in a reciprocal shift in hypothalamic neuropeptide Y (NPY) and GH-releasing hormone (GHRH) expression in the adult male rat. It is hypothesized that the fasting-induced rise in NPY is responsible for the GHRH decline and subsequent attenuation of pulsatile GH release. Fasting also leads to a decrease in circulating IGF-I, attributed to both reduced GH release and peripheral GH resistance. Although pituitary GH output is suppressed in the fasted rat, we report herein that pituitary GHRH receptor (GHRH-R) and GH secretagogue receptor (GHS-R) mRNA levels are increased, while pituitary expression of the somatostatin receptor subtype 2 (sst2) and 5 (sst5) is decreased, as determined by real-time reverse transcription (RT)-PCR. A shift in the expression of pituitary receptor subtypes to favor GH synthesis and release may be due, at least in part, to a decline in GH/IGF-I negative feedback. In order to test this hypothesis, we compared hypothalamic and pituitary response to fasting (72 h) in normal male rats and rats with isolated GH deficiency (spontaneous dwarf rats (SDR)). Circulating GH levels were undetectable in SDR, and IGF-I levels were less than 10% of normal controls. Fasting stimulated NPY mRNA levels in SDR; however, the rise in NPY mRNA levels was not accompanied by a fall in GHRH mRNA, as observed in fasted normal rats. In fact, GHRH mRNA levels paradoxically rose in the fasted SDR to 135% of fed controls. At the pituitary level, fasting did not alter sst2 and sst5 mRNA levels in SDR but did stimulate the expression of GHRH-R and GHS-R to 165% and 149% of fed controls, respectively. These results demonstrate that the fasting-induced changes in pituitary expression of sst2 and sst5, but not GHRH-R and GHS-R, are GH/IGF-I dependent. In addition, these results argue against the theory that the negative association of NPY and GHRH expression observed following fasting represents a simple cause-and-effect relationship and suggest that GH, either directly or indirectly, mediates the effects of fasting on hypothalamic GHRH expression.

Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes

“…injection) also lose weight and exhibit a dramatic reduction in circulating GH and IGF-I and a decrease in pituitary GH and hypothalamic GHRH expression, which is associated with pituitary GHRH hypersensitivity, in vitro (Murao et al 1995). It should be noted that these changes in the GH axis are strikingly similar to those observed in the fasted rat (Park et al 2004, Tannenbaum et al 1979) and therefore might be related to the catabolic condition and not to the absolute circulating levels of insulin and glucose. This hypothesis is consistent with a report showing BALB/c mice, when treated with a single i.v.…”

“…Hypothalamic GHRH, SRIH and NPY mRNA levels were measured by RPA using the HybSpeed RPA kit (Ambion, Austin, TX, USA) as previously described (Park et al 2004). Briefly, in a single reaction, probes for GHRH, SRIH, NPY and -actin were incubated for 20 min at 68 C in 10 µl HybSpeed Hybridization Buffer containing 50% total RNA isolated from a single hypothalamus or 50 µg yeast RNA.…”

Fasting in mood disorders: neurobiology and effectiveness. A review of the literature

“…Prolonged fasting (>8 d) is a strong physiological stimulus equivalent to a biological stress, that activates the hypothalamic-pituitary-adrenal axis (HPA, said "stress axis") (Brecchia et al, 2006;Fekete et al, 2006;Kim et al, 2008;Park et al, 2004;Shahab et al, 1997;Steiner et al, 2003). The biological mechanisms of this activation are unclear and could include the reduced availability of cerebral glucose, reduced insulin and leptin levels, or the sensation of hunger (Brecchia et al, 2006;Fekete et al, 2006;Kim et al, 2008;Park et al, 2004;Shahab et al, 1997;Steiner et al, 2003).…”

“…The biological mechanisms of this activation are unclear and could include the reduced availability of cerebral glucose, reduced insulin and leptin levels, or the sensation of hunger (Brecchia et al, 2006;Fekete et al, 2006;Kim et al, 2008;Park et al, 2004;Shahab et al, 1997;Steiner et al, 2003). Change in leptin levels has been identified as a strong signal of biological adaptation of the organism to starvation, and has been associated with mood disorders (Tichomirowa et al, 2005).…”

Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson's disease

“…Quantitative real-time PCR analysis was carried out with SYBR Green I and specific primers for TNF-a (NM_013693; sense, 5 0 -CCC AGA CCC TCA CAC TCA GAT-3 0 ; antisense, 5 0 -AAC ACC CAT TCC CTT CAC AGA-3 0 ), IL-1b (NM_008361; sense, 5 0 -ACC TTT TGA CAG TGA TGA GAA-3 0 ; antisense, 5 0 -AAG ATG AAG GAA AAG AAG GTG-3 0 ), proMMP-3 (NM_010809; sense, 5 0 -GAT CTC TTC ATT TTG GCC ATC TCT TC-3 0 ; antisense, 5 0 -CTC CAG TAT TTG TCC TCT ACA AAG AA-3 0 ), and b-actin (NM_031144; sense, 5 0 -ATG GGT CAG AAG GAC TCC TAC G-3 0 ; antisense, 5 0 -AGT GGT ACG ACC AGA GGC ATA C-3 0 ). Details of the procedure for real-time PCR were as previously described (Park et al 2004). …”