The GH/IGF-I axis in obesity: influence of neuroendocrine and metabolic factors

Abstract

In this review we propose an integrated neuro-endocrine-metabolic point of view on the alterations (adaptations?) of GHaIGF-1 axis in obesity, summarizing the evidence from the literature, particularly focusing the data on humans and adding where possible results from our studies in this ®eld. It is well-known that GH secretion is deeply impaired in overweight patients: we reviewed the multiple mechanisms underlying this issue, considering either central (CNS-related, such as impairment of GHRH tone or increased somatostatin release) or peripheral (ie metabolic: insulin, free fatty acids, glucose) factors. A central point of the debate about GH insuf®ciency in obesity is if it represents a simple adaptive phenomenon or re¯ects a true impairment of the axis activity. Evaluation of IGF-I levels and generation in obesity was the mean used to address this question: a bulk of evidence on IGF-I balance in human obesity has been provided, but the matter is still uncertain and unsolved.

Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency

“…Hypothalamic somatostatin hyperactivity seems unlikely, 5 but there is evidence for reduced activity of GHRH-secreting neurons, 5 although short-term treatment with GHRH does not restore the GH response to GHRH itself. 15 Abnormalities in peripheral hormones and metabolic factors could play a major role in making somatotroph cells and=or neuroendocrine mechanisms refractory to starvation. 10,29 -32 After fasting total IGF-I levels underwent a slight decrease in obese as well as in normal subjects who, however, showed striking increase in mGHc.…”

“…10,11 Fasting strikingly stimulates somatotroph secretion in normal healthy humans; 12,13 reduction in the negative IGF-I feedback action as well as CNS-mediated mechanisms such as concomitant reduction in somatostatin activity and GHRH hyperactivity are likely to play major role. 14,15 Somatotroph insufficiency in obesity is reversible after long-term diet-induced weight loss, 16 but the effect of fasting is still controversial. Short-term fasting has been reported to be able to enhance, but not restore, the GH response to GHRH as well as long-term diet does.…”

Correlates of obesity in postmenopausal women with breast cancer: comparison of genetic, demographic, disease-related, life history and dietary factors

“…Hyperinsulinemia, increased free IGF and increased circulating estrogen have each been associated with obesity in postmenopausal women. 13,14,21 Progesterone can induce the insulin and IGF-1 signaling cascades. 16 Steroid hormone receptor coactivators, such as AIB1, mediate gene expression by steroid hormones such as estrogen and progesterone.…”

“…14 Two genes that mediate the interactions between the estrogen, insulin and IGF signaling pathways are the progesterone receptor (PR) and the steroid hormone receptor coactivator pCIP/ACTR/AIB1/TRAM1/RAC3 (AIB1). [16][17][18][19][20][21] The AIB1 gene is amplified in about 10% of breast tumors, while its mRNA is overexpressed in about 64%. 18,22 Both the PR and AIB1 regulate both ER-and IGF-mediated gene transcription.…”

Aspectos neuroendócrinos da síndrome metabólica

“…Além disso, a fração livre do IGF-1 é a responsável pelo crescimento normal dos adolescentes obesos, que apresentam níveis diminuídos de GH, IGF-1 total e IGFBPs. Desta forma, discute-se hoje se a SM pode ser realmente considerada um estado de hipo-somatotropismo ou se os mecanismos compensatórios são suficientes para preservar ações primárias do GH, principalmente em crianças e adolescentes (60).…”