ReviewThe metabolic role of growth hormone in humans with particular reference to fasting
Introduction
Throughout history starvation has been a major threat to survival of the human species. Most inhabitants of the Western world are not accustomed to shortage of food but hunger remains a major global problem. Today, United Nations estimate that more than 800 million people in the world are chronically starving and malnourished and nine million men, women and children perish annually from hunger, starvation, disease and malnutrition (World Food Programme 2004).
The response to absolute deprivation of food proceeds in a number of stages, and the body can survive for around two months without any food intake as a result of coordinated regulation of metabolism [1]. During fasting, adipose tissue, muscle, liver and kidneys work in concert to supply, to convert, and to conserve fuels for the body. During the brief postabsorptive period of around 6 h, blood fuel homeostasis is maintained primarily by hepatic glycogenolysis and adipose tissue lipolysis. As fasting progresses, muscle proteolysis supplies gluconeogenic amino acids for hepatic gluconeogenesis. After a few days of starvation, the metabolic profile is set to conserve protein and to supply increased quantities of alternative fuels. In particular, free fatty acids and ketone bodies are utilized to maintain energy supplies.
During fasting and stress, growth hormone (GH) secretion is augmented [2], and these conditions may thus be viewed as the natural metabolic domain for GH action. The reciprocal association between insulin and GH (the feast–famine cycle) and its potential implications for substrate metabolism was initially recognised by Rabinowitz and Zierler [3], but surprisingly few studies of the metabolic impact of GH during fasting have been conducted. The metabolic effects of GH are complex and involve increased lipolysis, protein retention, impaired suppression of hepatic glucose production and decreased insulin-dependent glucose disposal, hyperglycemia, hyperinsulinemia, stimulation of IGF-I activity, and changes in body composition [4], [5], [6], [7], [8]. The degree to which potential secondary mediators contribute to the metabolic action of GH during fasting has not been completely investigated.
To outline the effects of GH on substrate metabolism during energy restriction the present thesis will review existing knowledge about the topic. The possible mechanisms underlying the metabolic effects of GH will be discussed.
Section snippets
The physiology of growth hormone secretion
Endogenous GH secretion rates are enhanced 5-fold by a 2-day fast in normal young men [2]. The metabolic and hormonal mechanisms by which nutritional deprivation affects the hypothalamic–somatotroph axis are not completely clarified. Until recently the regulation of GH release was believed to represent the net result of the antagonistic actions of hypothalamic growth hormone releasing hormone (GHRH) and somatostatin (SRIF) on the pituitary, as well as negative feedback via circulating IGF-I [9]
GH receptor and postreceptor signalling
Growth hormone receptors have been identified in many tissues including muscle, adipose tissue, liver, heart, kidney, brain and the pancreas [47], [48]. GH binds to a membrane receptor (GHR) which is part of the cytokine receptor superfamily [49]. The GHR exists in three forms, the full-length, long form composed of 620 amino acids, and two short forms of either 277 or 279 amino acids in length [50]. One of the short forms is membrane-bound, with a much shorter cytoplasmic domain. The soluble
Metabolic adaptation to starvation
Classic studies by Benedict [65] and Cahill [66], [67] have partly clarified the complex nature of the metabolic adaptations to starvation. More than 80 years ago Benedict [65] fasted a normal subject for 30 days, and by indirect calorimetry and measurement of excreted nitrogen found carbohydrate to provide only a small percentage of the body’s fuel, mainly for the first few days. Thereafter fat provided over 3/4 of the daily caloric consumption and protein the remainder. Benedict was unaware
Impact of GH on protein metabolism
Efforts to study the regulation of protein synthesis and degradation in vivo have been extended to include methods that examine the activity of the pathways involved (e.g., mRNA transcription and activation of translational regulatory elements). In particular the regulation of proteolysis is not fully understood, in part because of the complexity of the pathways involved in protein degradation. The bulk of all intracellular protein is degraded by the ubiquitin–proteasome pathway [106], [107].
Impact on insulin sensitivity
It is well described that prolonged fasting induces insulin resistance [70], which may be related to high circulating levels of GH [76]. Because GH promotes lipolysis in adipose tissue and elevation of GH is associated with increased plasma free fatty acid level [160], [174], [197], increased lipid availability has been suggested to be responsible for the insulin resistance observed with elevated GH levels. Neely have shown that after an overnight GH infusion in normal subjects, both GH and FFA
General conclusions
GH is traditionally considered of main importance for linear growth in childhood but the metabolic actions continue in adulthood. GH secretion is increased under conditions of fasting and stress and it is likely that GH exerts its major impact under such conditions. The mechanisms by which GH regulates metabolism are complex and include stimulation of lipolysis and increased fat utilisation, stimulation of the IGF-I system, insulin resistance and hyperinsulinemia, and protein conservation.
GH
References (320)
- et al.
Free insulin-like growth factors (IGF-I and IGF-II) in human serum
FEBS Lett.
(1994) - et al.
Evidence supporting a direct suppressive effect of growth hormone on serum IGFBP-1 levels. Experimental studies in normal, obese and GH-deficient adults
Growth Horm. IGF Res.
(1999) - et al.
A-like cells in the rat stomach contain ghrelin and do not operate under gastrin control
Regul. Pept.
(2001) - et al.
Upregulation of ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration
Biochem. Biophys. Res. Commun.
(2001) - et al.
Somatostatin suppresses ghrelin secretion from the rat stomach
Biochem. Biophys. Res. Commun.
(2003) - et al.
Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase
Cell
(1993) - et al.
Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo
J. Biol. Chem.
(1994) - et al.
Intermittent plasma growth hormone triggers tyrosine phosphorylation and nuclear translocation of a liver-expressed, Stat 5-related DNA binding protein
J. Biol. Chem.
(1995) - et al.
Growth hormone, but not insulin, activates STAT5 proteins in adipocytes in vitro and in vivo
Biochem. Biophys. Res. Commun.
(2003) - et al.
Growth hormone, interferon-γ, and leukemia inhibitory factor promoted tyrosyl phophorylation of insulin receptor substrate-1
J. Biol. Chem.
(1995)
The effect of starvation on insulin-induced glucose disposal and thermogenesis in humans
Metabolism
Leucine, glucose, and energy metabolism after 3 days of fasting in healthy human subjects
Am. J. Clin. Nutr.
Metabolic regulation. A human perspective
Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men
J. Clin. Endocrinol. Metab.
A metabolic regulating device based on the actions of human growth hormone and of insulin singly and together on the human forearm
Nature
The effect of growth hormone on glucose metabolism and insulin secretion in man
J. Clin. Endocrinol. Metab.
Effects of growth hormone on insulin action in man. Mechanisms of insulin resistance, impaired suppression of glucose production, and impaired stimulation of glucose utilization
Diabetes
Acute growth hormone effects on amino acid and lipid metabolism
J. Clin. Endocrinol. Metab.
Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles
Annu. Rev. Physiol.
Growth hormone therapy in adults
Annu. Rev. Med.
Physiological regulators of growth hormone secretion
Ghrelin is a growth-hormone-releasing acylated peptide from stomach
Nature
Plasma somatomedin-C in fasted and refed rats: close relationship with changes in the liver somatogenic but not lactogenic binding sites
J. Endocrinol.
Nutritional-induced changes in hepatic insulin-like growth factor I (IGF-I) gene expression in rats
Endocrinology
Regulation by fasting of rat insulin-like growth factor I and its receptor. Effects on gene expression and binding
J. Clin. Invest.
Impairment of liver GH receptor signaling by fasting
Endocrinology
Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary
Science
Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man
J. Clin. Invest.
A low dose euglycemic infusion of recombinant human insulin-like growth factor I rapidly suppresses fasting-enhanced pulsatile growth hormone secretion in humans
J. Clin. Invest.
Recombinant human insulin-like growth factor (IGF)-binding protein-1 inhibits somatic growth stimulated by IGF-I and growth hormone in hypophysectomized rats
Endocrinology
Regulation and function of insulin-like growth factor-binding protein-1
Proc. Soc. Exp. Biol. Med.
The effect of oral glucose on serum free insulin-like growth factor-I and -II in healthy adults
J. Clin. Endocrinol. Metab.
Development and clinical evaluation of a novel immunoassay for the binary complex of IGF-I and IGF-binding protein-1 in human serum
J. Clin. Endocrinol. Metab.
The effect of growth hormone on the insulin-like growth factor system during fasting
J. Clin. Endocrinol. Metab.
Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans
Endocrinology
The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion
Endocrinology
Ghrelin strongly stimulates growth hormone release in humans
J. Clin. Endocrinol. Metab.
Splanchnic release of ghrelin in humans
J. Clin. Endocrinol. Metab.
Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans
J. Clin. Endocrinol. Metab.
Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery
N. Engl. J. Med.
A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans
Diabetes
Post-prandial decrease of circulating human ghrelin levels
J. Endocrinol. Invest.
Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion
J. Clin. Endocrinol. Metab.
Circulating ghrelin levels are decreased in human obesity
Diabetes
Weight gain decreases elevated plasma ghrelin concentrations of patients with with anorexia nervosa
Eur. J. Endocrinol.
Ghrelin drives GH secretion during fasting in man
Eur. J. Endocrinol.
Ghrelin immunoreactivity in human plasma is suppressed by somatostatin
Clin. Endocrinol.
Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans
J. Clin. Endocrinol. Metab.
Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels
J. Clin. Endocrinol. Metab.
Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Praeder–Willi syndrome
J. Clin. Endocrinol. Metab.
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