Understanding the role of growth hormone in situations of metabolic stress

in Journal of Endocrinology
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Mariana Rosolen Tavares Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil

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Renata Frazao Department of Anatomy, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil

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Jose Donato Jr Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, Brazil

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Correspondence should be addressed to J Donato Jr: jdonato@icb.usp.br
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Growth hormone (GH) is secreted by the anterior pituitary gland and plays a key role in controlling tissue and body growth. While basal GH secretion is considerably reduced along adulthood and aging, several situations of metabolic stress can lead to robust increases in circulating GH levels. The objective of the present review is to summarize and discuss the importance of GH regulating different physiological functions in situations of metabolic stress, including prolonged food restriction, hypoglycemia, exercise, pregnancy, and obesity. The presented data indicate that GH increases hunger perception/food intake, fat mobilization, blood glucose levels, and insulin resistance and produces changes in energy expenditure and neuroendocrine responses during metabolic challenges. When all these effects are considered in the context of situations of metabolic stress, they contribute to restore homeostasis by (1) helping the organism to use appropriate energy substrates, (2) preventing hypoglycemia or increasing the availability of glucose, (3) stimulating feeding to provide nutrients in response to energy-demanding activities or to accelerate the recovery of energy stores, and (4) affecting the activity of neuronal populations involved in the control of metabolism and stress response. Thus, the central and peripheral effects of GH coordinate multiple adaptations during situations of metabolic stress that ultimately help the organism restore homeostasis, increasing the chances of survival.

Abstract

Growth hormone (GH) is secreted by the anterior pituitary gland and plays a key role in controlling tissue and body growth. While basal GH secretion is considerably reduced along adulthood and aging, several situations of metabolic stress can lead to robust increases in circulating GH levels. The objective of the present review is to summarize and discuss the importance of GH regulating different physiological functions in situations of metabolic stress, including prolonged food restriction, hypoglycemia, exercise, pregnancy, and obesity. The presented data indicate that GH increases hunger perception/food intake, fat mobilization, blood glucose levels, and insulin resistance and produces changes in energy expenditure and neuroendocrine responses during metabolic challenges. When all these effects are considered in the context of situations of metabolic stress, they contribute to restore homeostasis by (1) helping the organism to use appropriate energy substrates, (2) preventing hypoglycemia or increasing the availability of glucose, (3) stimulating feeding to provide nutrients in response to energy-demanding activities or to accelerate the recovery of energy stores, and (4) affecting the activity of neuronal populations involved in the control of metabolism and stress response. Thus, the central and peripheral effects of GH coordinate multiple adaptations during situations of metabolic stress that ultimately help the organism restore homeostasis, increasing the chances of survival.

Introduction

Among the different endocrine cells present in the pituitary gland, somatotrophs are considered the most abundant, representing approximately 40% of the total number of cells (Ruf-Zamojski et al. 2021). Somatotrophs produce growth hormone (GH), a protein that contains 191 amino acids and 22 kDa. GH is secreted in a pulsatile manner under the control of neuropeptides released by hypothalamic neurons. The hypothalamic secretion of GH-releasing hormone (GHRH) stimulates pituitary GH release, whereas somatostatin inhibits it (Murray et al. 2015, Steyn et al. 2016). The stomach-derived hormone ghrelin is also a powerful GH secretagogue (Kojima et al. 1999, Murray et al. 2015, Steyn et al. 2016).

The classical and most known effect of GH is the stimulation of tissue and body growth. Early life deficiency of GH or GH receptor (GHR) causes dwarfism, whereas GH oversecretion induces gigantism (Devesa et al. 2016, Dehkhoda et al. 2018, Ranke & Wit 2018). Elevated GH secretion in adulthood, normally induced by pituitary tumors, leads to acromegaly. GH induces anabolic effects in numerous tissues by stimulating protein synthesis and cell proliferation (Devesa et al. 2016, Dehkhoda et al. 2018, Ranke & Wit 2018). These effects are partially mediated by insulin-like growth factor 1 (IGF-1), whose expression is induced by GHR activation. GHR signaling stimulates IGF-1 expression in different tissues, but circulating IGF-1 levels are mainly controlled by the liver (Murray et al. 2015, Devesa et al. 2016, Steyn et al. 2016, Dehkhoda et al. 2018, Ranke & Wit 2018). The absence of GHR in hepatocytes causes a profound reduction in circulating IGF-1 levels, which decreases body growth, although without causing dwarfism (List et al. 2014).

Maximal GH secretion is observed during childhood and adolescence and progressively decreases in adulthood. Older (>55 years old) individuals exhibit decreases in mean GH levels, GH pulse amplitude, and the number of large GH pulses, compared to young (18–33 years old) adults (Ho et al. 1987). The high GH secretion in children and adolescents is in accordance with the well-documented role of GH in stimulating tissue and body growth. So, what would be the function of GH in adults when its basal secretion is decreased and the final stature has already been reached? Different situations of acute or chronic stress are known to induce a robust GH secretion. This is particularly evident in situations of metabolic stress, such as hypoglycemia (Roth et al. 1963), prolonged food deprivation (Zhao et al. 2010), physical exercise (Veldhuis et al. 2015), and even pregnancy (Gatford et al. 2017), which is a condition that requires numerous metabolic adaptations to the increasing energy demands of the fetus(es). In the present review, we summarize the metabolic effects of GH in the context of situations of stress. Our objective is to postulate that the different metabolic effects of GH, both at the level of the CNS and the periphery, ultimately aim to restore homeostasis, increasing the chances of survival when the organism is challenged by situations of metabolic stress.

Metabolic effects of GH

GH induces insulin resistance and regulates glucose homeostasis

Classical studies have shown that the anterior pituitary lobe produces hormone(s) that affect(s) the metabolism of sugar, impairing the effects of insulin (Houssay & Biasotti 1931). These findings led Bernardo A Houssay to receive in 1947 the Nobel Prize in Physiology or Medicine. The diabetogenic effect of pituitary extracts was later attributed to the specific role of GH (Ranke & Wit 2018). GH or GHR deficiency increases insulin sensitivity, whereas GH oversecretion, like in acromegaly, induces insulin resistance and diabetes (Luger et al. 1990, Takahashi et al. 2001, Rose & Clemmons 2002, Moller & Jorgensen 2009). In this sense, GH stimulates hepatic gluconeogenesis and glucose production (Rizza et al. 1982, De Feo et al. 1989, Dehkhoda et al. 2018) (Fig. 1). In the skeletal muscle, GH induces insulin resistance and decreases glucose uptake (Yakar et al. 2004, Moller & Jorgensen 2009, Krusenstjerna-Hafstrom et al. 2011) (Fig. 1). GHR ablation in white adipocytes increases systemic insulin sensitivity, despite favoring body fat accumulation (List et al. 2019). Therefore, GHR signaling in several insulin-sensitive tissues produces the diabetogenic effect of GH. However, it is important to stress that the effect of GH on insulin sensitivity in different tissues may be either direct or indirect, as discussed in more detail in other parts of this manuscript and elegantly reviewed by Vazquez-Borrego et al. (2021).

Figure 1
Figure 1

Summary of the effects of GH in different tissues. These effects can be caused either by direct action of GH or through indirect mechanisms. Direct effects mean that they are mediated by GHR signaling in that tissue. Example of indirect effect is the insulin resistance in the liver and muscle caused by the increased GH-induced lipolysis in the white adipose tissue.

Citation: Journal of Endocrinology 256, 1; 10.1530/JOE-22-0159

GH also regulates glucose homeostasis by acting in other tissues. GHR expression in β-cells induces hyperplasia and regulates glucose-stimulated insulin secretion (Fig. 1) (Wu et al. 2011). Hypophysectomized dogs are prone to develop severe hypoglycemia (Houssay & Biasotti 1931). GHR deficiency also causes transient juvenile hypoglycemia (Hinrichs et al. 2021). Accordingly, reduced GH secretion is associated with a higher prevalence of episodes of spontaneous hypoglycemia (Hussain et al. 2003). Thus, it is clear the important role of GH in the prevention of hypoglycemia.

Not only does GH prevent hypoglycemia by antagonizing the glucose-lowering effects of insulin but glucose-sensitive neurons in the hypothalamus are also directly responsive to GH (Fig. 2) (Furigo et al. 2017, 2019a, Wasinski et al. 2021b). Previous studies have shown that systemic GH injection can induce the phosphorylation of the signal transducer and activator of transcription 5 (pSTAT5) in a large number of neurons in the ventromedial nucleus of the hypothalamus (VMH) (Furigo et al. 2017, 2019a, Wasinski et al. 2021b). Since the activation of GHR recruits and phosphorylates STAT5 protein, neurons that exhibit pSTAT5 after an acute GH injection supposedly express functional GHR. VMH neurons respond to variations in blood glucose levels and they are part of the neurocircuit that is recruited during hypoglycemia to induce a counter-regulatory response (CCR) (Verberne et al. 2014). Mice carrying GHR ablation in cells comprising the VMH exhibit impaired capacity to recover from insulin-induced hypoglycemia (Furigo et al. 2019a). This occurs because their ability to induce the CCR is reduced. The blockade of the parasympathetic nervous system prevents the impaired CCR observed in VMH-specific GHR knockout (KO) mice (Furigo et al. 2019a). Thus, GH prevents hypoglycemia either by counteracting the effects of insulin or by targeting hypothalamic neurons involved in the CCR (Fig. 2).

Figure 2
Figure 2

Neuronal populations that are responsive to GH and the described effects of GH receptor signaling in each one. The photomicrographs show neurons expressing pSTAT5 (magenta nuclear staining) after an acute GH stimulus. The cytoplasm of AgRP or POMC neurons is labeled in green. Double-labeled neurons appear as white or are indicated by the arrows. 3V, third ventricle; ARH, arcuate nucleus of the hypothalamus; VMH, ventromedial nucleus of the hypothalamus.

Citation: Journal of Endocrinology 256, 1; 10.1530/JOE-22-0159

GH stimulates fat mobilization

GH injection increases lipolysis in the adipose tissue (Kopchick et al. 2020), leading to an elevation in free fatty acid (FFA) levels in the bloodstream (Fig. 1). In contrast, GH or GHR deficiency increases fat accumulation in white adipose tissue, particularly in subcutaneous depots (Kopchick et al. 2020). Biochemical control of acromegaly increases both subcutaneous and visceral adipose tissue cross-sectional area (Bredella et al. 2017). GH probably acts directly in the adipose tissue to stimulate lipolysis since adipocyte-specific GHR KO mice exhibit increased fat accumulation (List et al. 2019). There is evidence linking the lipolytic effect of GH with insulin resistance (Kopchick et al. 2020). In this regard, the blockade of lipolysis is sufficient to prevent the insulin resistance that occurs during GH administration (Nielsen et al. 2001). Indeed, elevated fatty acid flux to insulin-sensitive tissues is associated with the development of insulin resistance and diabetes in obesity and overfeeding (Petersen & Shulman 2018).

GH stimulates hunger

Growth is an energy-demanding process. Thus, from an evolutionary point of view, it makes sense to associate growth with increased hunger. Although the physiological role of GH in the CNS is just starting to be uncovered, several pieces of evidence indicate that GH has a central orexigenic effect. For example, intracerebroventricular injection of GH stimulates 24 h food intake in mice (Furigo et al. 2019b). GH overexpression in the mouse CNS causes hyperphagia and obesity (Bohlooly et al. 2005). Increased GH secretion in transgenic carp also leads to higher food intake (Zhong et al. 2013). Chemogenetic activation of neurons that express GHR in the arcuate nucleus of the hypothalamus (ARH) also stimulates food intake (de Lima et al. 2021a).

Hypothalamic neurons that express agouti-related peptide (AgRP) are key regulators of food intake (Andermann & Lowell 2017). Accordingly, chemogenetic activation of AgRP neurons causes a potent increase in food intake (Krashes et al. 2011). Importantly, AgRP-expressing neurons represent another neuronal population highly responsive to GH (Fig. 2). The orexigenic effect of GH is likely mediated by AgRP neurons because GH induces depolarization of a subset of AgRP neurons (Furigo et al. 2019b). In addition, systemic GH infusion increases Agrp mRNA levels in the mouse hypothalamus (Furigo et al. 2019b). GH overexpression in the brain also increases hypothalamic Agrp mRNA levels (Bohlooly et al. 2005). Even in fish, GH overproduction induces upregulation of Agrp mRNA levels in the hypothalamus (Zhong et al. 2013). Therefore, GHR signaling in hypothalamic AgRP neurons probably plays a critical role in the orexigenic effect of GH.

Situations of low-energy availability frequently induce hunger. This includes hypoglycemia (Ikeda et al. 1980), food restriction (Pedroso et al. 2016), and post-physical exercise (Cavalcanti-de-Albuquerque & Donato 2021). GHR ablation either in AgRP – or proopiomelanocortin (POMC) – expressing neurons (Fig. 2) reduces glucoprivic hyperphagia (Furigo et al. 2019b, Quaresma et al. 2019), indicating that GH secretion during hypoglycemia probably represents a circulating signal that induces food intake, contributing to the recovery of blood glucose levels. Hyperphagia is also typically observed when animals regain access to food after fasting or food restriction (Pedroso et al. 2016). Notably, neuron-specific GHR KO mice show reduced hyperphagia after fasting or 5 days of food restriction (Wasinski et al. 2021a). Pregnancy is associated with increased food intake (Zampieri et al. 2015). Neuron-specific GHR ablation also reduces food intake in pregnant mice suggesting that at least part of pregnancy-induced hyperphagia is driven by central GHR signaling (Teixeira et al. 2019).

Ghrelin is known as the ‘hunger hormone’ because an acute ghrelin injection stimulates food intake, even in satiated animals (Tschop et al. 2000, Nakazato et al. 2001). Although previous studies indicate that the activation of the ghrelin receptor in AgRP-expressing neurons is underlying the orexigenic effect of ghrelin (Wang et al. 2014), recent studies suggest that GH action is necessary for the feeding response to ghrelin. Neuron-specific GHR ablation prevents the feeding response induced by an acute ghrelin injection in mice (Wasinski et al. 2021a). Dwarf GHR-deficient mice also exhibit a blunted feeding response to ghrelin (Egecioglu et al. 2006). Another study showed that somatotroph-specific ghrelin receptor deletion not only prevents ghrelin-induced GH secretion but also the orexigenic effect of ghrelin (Gupta et al. 2021). Thus, through still unknown mechanisms, GH secretion or central GHR signaling is required for the orexigenic effect of ghrelin.

GH regulates energy expenditure and thermogenesis

GH deficiency increases body fat content, while the percentage of lean mass is decreased (Kopchick et al. 2020). These alterations in body composition may lead to changes in energy expenditure since they affect metabolically relevant tissues. Although some studies have shown that GH-deficient adults have normal energy metabolism when corrected for body composition (Hoffman et al. 1995, Deepak et al. 2008), other studies indicate that GH replacement in GH-deficient patients or obese individuals increases both lean body mass and resting energy expenditure (Jorgensen et al. 1994a,b, Momozono et al. 2021). Additionally, GH treatment stimulates peripheral T4 to T3 conversion in a dose-dependent manner (Jorgensen et al. 1994a,b). GH replacement in GH-deficient adults also increases hunger ratings (Deepak et al. 2008). Thus, GH administration in obese or GH-deficient individuals can stimulate energy expenditure by increasing (1) lean body mass and therefore the amount of metabolically active tissues; (2) the activity of thyroid hormones, by converting T4 to its active form (T3); and (3) food consumption, which can also increase energy expenditure.

In contrast, there is evidence that central GH action decreases energy expenditure during prolonged food restriction (Furigo et al. 2019b). As previously mentioned, GH depolarizes AgRP neurons (Furigo et al. 2019b), and the activation of AgRP neurons suppresses energy expenditure (Krashes et al. 2011). During 5 days of calorie restriction, mice exhibit a progressive decrease in energy expenditure as an adaptive response to prolonged food deprivation (Furigo et al. 2019b). In starved animals, physiological processes that expend energy are suppressed, including the thyroid axis and the reproductive system. The usual activation of AgRP neurons during fasting or food restriction is blunted in mice carrying an AgRP-specific GHR ablation (Furigo et al. 2019b, de Lima et al. 2021b). Moreover, fasting-induced hypothalamic upregulation of sirtuin 1, a key nutrient-sensing protein, is blunted in mice carrying GHR deletion in AgRP neurons (de Lima et al. 2021b). Consequently, the neuroendocrine adaptations that save energy during food restriction are mostly prevented, resulting in elevated energy expenditure in AgRP-specific GHR KO mice, even after several days of severe calorie restriction (Furigo et al. 2019b). Furthermore, administration of pegvisomant, a GHR antagonist, can increase the energy expenditure of food-deprived wild-type mice, similar to leptin (Furigo et al. 2019b). Accordingly, the activation of ARHGHR neurons suppresses heat production in fasted mice (de Lima et al. 2021a). Thus, at the level of CNS, GH acts as a starvation signal that induces energy-saving adaptations during prolonged food restriction via activation of ARHAgRP neurons.

The role of GH in situations of metabolic stress

As previously mentioned, during childhood and adolescence, a high GH secretion induces anabolic effects, favoring protein synthesis, cell proliferation, and tissue/body growth. Thus, during development, GH acts synergistically with insulin and IGF-1 to induce growth (Fig. 3). In contrast, during situations of metabolic stress, GH mostly acts in such a way to antagonize the effects of insulin (Fig. 3). So, while insulin inhibits lipolysis and hepatic glucose production and increases glucose uptake, GHR signaling in different tissues causes opposite effects. In this section, we intend to discuss how the different central and peripheral effects of GH converge during situations of metabolic stress to ultimately help the organism to restore homeostasis and increase the chances of survival.

Figure 3
Figure 3

GH can have either synergic or antagonistic effects on insulin, depending on the situation.

Citation: Journal of Endocrinology 256, 1; 10.1530/JOE-22-0159

Prolonged food deprivation

The lack of enough food is a major metabolic challenge that is frequently faced by animals in the wild. Numerous metabolic adaptations are necessary to improve the chances of survival during prolonged food deprivation. First, hunger is induced to motivate animals to seek food. In parallel, changes in energy partitioning take place to favor the use of fat as the primary energy source, at the same time endogenous glucose production is necessary to supply this critical nutrient to glucose-dependent cells. Additionally, energy-demanding processes are progressively suppressed, so the animals will have more time to find food before dying of starvation.

Fasting or food restriction increases acyl-ghrelin levels (Luque et al. 2007, Zhao et al. 2010, Gupta et al. 2021). Mice deficient in acyl-ghrelin show a blunted increase in GH levels during food deprivation (Zhao et al. 2010). The rise in GH levels is also prevented in food-deprived mice that are deficient in the ghrelin receptor in somatotropic cells (Gupta et al. 2021), which further indicates that ghrelin is responsible for inducing the increase in GH secretion during food deprivation. Another study in mice showed that hypothalamic Ghrh mRNA expression is upregulated after 12 or 24 h of fasting, but this transcript is suppressed after 48 h of fasting (Luque et al. 2007). Neuropeptide Y-expressing neurons are likely involved in this neuroendocrine response since hypothalamic Ghrh mRNA expression remained unaltered in mice knockout for the Npy gene after 48 h of fasting (Luque et al. 2007). Pituitary changes can also contribute to the elevation of GH secretion during fasting, which includes an increase in the pituitary expression of GHRH and ghrelin receptors, whereas somatostatin receptors 2, 3, and 5 are downregulated in fasted mice (Luque et al. 2007).

GH action in different tissues is critically involved in the metabolic adaptations to starvation (Fig. 4). Some studies have shown that the absence of GH action can compromise survival (Zhao et al. 2010, Furigo et al. 2019b). Mice deficient in acyl-ghrelin develop profound hypoglycemia when exposed to severe calorie restriction (Zhao et al. 2010). This defect is associated with reduced GH secretion during food restriction due to the lack of GH secretagogue function of acyl-ghrelin. GH replacement during prolonged calorie restriction prevents hypoglycemia in mice deficient in acyl-ghrelin (Zhao et al. 2010). Defects in the ghrelin–GH axis decrease hepatic gluconeogenesis in starved mice, helping to explain the development of hypoglycemia (Li et al. 2012). Central GH action is also involved in the control of hypoglycemia during food deprivation since GHR ablation in AgRP-expressing neurons leads to reduced glycemia in starved mice (Furigo et al. 2019b). However, mice with adult-onset GH deficiency can sustain blood glucose levels to 82–85% of ad libitum-fed values, even after 11 days of food restriction (Gahete et al. 2013). Recent evidence indicates that IGF-1 levels play a major role in the maintenance of blood glucose during starvation (Fang et al. 2022).

Figure 4
Figure 4

Scheme illustrating how GH action in the periphery and CNS coordinates multiple adaptations that help to restore homeostasis during situations of metabolic stress, such as prolonged food restriction, hypoglycemia, exercise, and pregnancy.

Citation: Journal of Endocrinology 256, 1; 10.1530/JOE-22-0159

Furthermore, GH secretion during food deprivation stimulates the use of fat as an energy source (Gahete et al. 2013) since it increases lipolysis, whereas GH inhibits glucose disposal by increasing insulin resistance and therefore decreasing glucose uptake in muscle and adipose tissue. Thus, the ‘lipolytic, gluconeogenic, and diabetogenic’ effects of GH coordinate multiple adaptations that help the organism to use appropriate energy substrates and prevent the development of hypoglycemia during starvation (Fig. 4).

Numerous pieces of evidence indicate that GH is an orexigenic hormone (Bohlooly et al. 2005, Deepak et al. 2008, Zhong et al. 2013, Furigo et al. 2019b, Quaresma et al. 2019, de Lima et al. 2021a, Wasinski et al. 2021a). Therefore, GH secretion during prolonged food restriction likely increases hunger perception and consequently the search for food (Fig. 4). In accordance with this idea, GHR ablation in neurons decreases food intake when mice are allowed to eat after 5 days of food restriction or 24 h of fasting (Wasinski et al. 2021a). Finally, GHR signaling in AgRP neurons favors the development of adaptive responses to food restriction, which ultimately suppresses energy expenditure (Furigo et al. 2019b, 2020, de Lima et al. 2021b). Without these energy-saving adaptations, the animals cannot tolerate prolonged calorie restriction since they present an early depletion of their body energy reserves, accelerating their death by starvation (Furigo et al. 2019b). Thus, GH acts on both sides of the energy balance equation during starvation, either by favoring the search/intake of food or decreasing the energy expenditure (Fig. 4). From an evolutionary point of view, these metabolic adaptations are critical to increasing the chances of survival.

Hypoglycemia

GH is robustly secreted during hypoglycemia (Roth et al. 1963). GH secretion is induced by glucose-sensing GHRH neurons that are activated by low glucose levels (Stanley et al. 2013). So, what is the role of GH in situations of glucopenia? As previously described, GH deficiency increases the prevalence of spontaneous hypoglycemia in animal models and humans (Houssay & Biasotti 1931, Hussain et al. 2003, Hinrichs et al. 2021). Thus, GH can be considered a counter-regulatory hormone that helps to prevent the development of hypoglycemia. In a similar way to food restriction, during hypoglycemia, the lipolytic, gluconeogenic, and diabetogenic effects of GH help to increase blood glucose levels by (1) sparing glucose use by providing FFA as an alternative energy source and through the induction of insulin resistance in the muscle and adipose tissue and (2) increasing hepatic glucose production (Fig. 4). GH can increase hepatic glucose production by inhibiting insulin action in the liver (direct and indirect action) and via the activation of the CCR, an effect likely mediated by GH-responsive neurons in the VMH (Furigo et al. 2019a).

It is unclear whether GH secretion during hypoglycemia can influence energy expenditure. However, the central activation of energy-saving adaptations could also decrease glucose disposal and therefore facilitate the recovery from hypoglycemia. Future studies are necessary to investigate this possibility. Situations of glucopenia usually induce an increase in hunger (Ikeda et al. 1980). This response is thought to be an additional way to recover from hypoglycemia, via intestinal absorption of glucose and other nutrients after feeding (Fig. 4). GH is also involved in this adaptation since GHR signaling in AgRP or POMC neurons is required for a normal glucoprivic hyperphagia (Furigo et al. 2019b, Quaresma et al. 2019).

Physical exercise

Exercise invariably increases energy expenditure either due to the demand for muscle contractions or organs that increase their activity, such as the heart and lungs. Exercise can increase GH secretion and circulating GH levels, particularly in young lean individuals (Kindermann et al. 1982, Cruzat et al. 2008, Weltman et al. 2008, Veldhuis et al. 2015). GH secretion is directly related to the intensity and duration of exercise (Kindermann et al. 1982, Cruzat et al. 2008, Weltman et al. 2008, Veldhuis et al. 2015). There is robust evidence indicating that exercise modifies hypothalamic circuits that control energy homeostasis (Cavalcanti-de-Albuquerque & Donato 2021). On the other hand, hypothalamic neurons play a key role in controlling numerous metabolic adaptations that affect muscle physiology and exercise performance (Cavalcanti-de-Albuquerque & Donato 2021). Accordingly, the activation of ARHGHR neurons increases glucose uptake and the expression of glycolytic enzymes in the skeletal muscle (de Lima et al. 2021a). Although this study did not investigate the consequences of these alterations during exercise, higher glucose utilization by the muscle can affect exercise performance. Changes in the sensitivity to cytokines in VMH neurons lead to alterations in training performance and glucose control during intense resistance exercise (Pedroso et al. 2017). It is believed that GH secretion contributes to exercise performance (Fig. 4). In line with this idea, GHR ablation in specific hypothalamic neurons affects the adaptation capacity to aerobic exercise (Pedroso et al. 2021).

GH increases the circulating levels of FFA and glucose, improving the energy supply for contracting muscle and other tissues. In terms of food intake, exercise usually suppresses feeding acutely, but chronic exercise increases food intake proportionally to the activity amount (Cavalcanti-de-Albuquerque & Donato 2021). Like GH, exercise can increase the activity of AgRP neurons (Landry et al. 2022), and AgRP neuronal activation is required for exercise-induced increases in food intake in mice (Bunner et al. 2020). Thus, considering that GH presents orexigenic effects and induces the activation of AgRP neurons (Furigo et al. 2019b), the increased food intake in response to exercise may be at least partially mediated by GH. This increase in hunger is a way of helping to recover the energy stores mobilized during exercise (Fig. 4).

Pregnancy

Pregnancy is a period characterized by marked metabolic changes. Food intake is increased as a result of the additional energy demands required for fetal growth (Zampieri et al. 2015, Teixeira et al. 2019). Pregnant animals also develop insulin resistance that is normally compensated by increased glucose-stimulated insulin secretion. Pregnancy-induced insulin resistance is likely an evolutionary adaptation that redirects glucose from the maternal organism to support fetal development. GH secretion is increased during pregnancy (Gatford et al. 2017). In humans, the placental GH variants represent the major isoforms secreted by pregnant women, while in rodents, that do not have the genes encoding the placental variants, GH levels are maintained elevated during pregnancy through the pituitary secretion in a pulsatile way (Gatford et al. 2017, Liao et al. 2018, Wasinski et al. 2022). GH secretion during pregnancy is associated with fetal growth and possible pregnancy complications (Liao et al. 2018). Key metabolic adaptations of pregnancy are linked with GH physiological functions (Fig. 4). In this regard, GH likely drives feeding during pregnancy. Accordingly, pregnancy-induced increase in food intake is partially prevented in mice carrying neuron-specific GHR ablation (Teixeira et al. 2019). Additionally, GHR deletion either in all neurons or only in leptin receptor-expressing cells decreases serum insulin levels and robustly improves insulin sensitivity during pregnancy in mice (Teixeira et al. 2019). Thus, changes in glucose and energy homeostasis during pregnancy are regulated by peripheral and central GH actions (Fig. 4). The effects of GH during pregnancy can be understood as beneficial from the point of view of improving fetal developmental conditions.

Obesity

Although obesity is not an acute situation of metabolic stress, the chronic energy imbalance and the consequent accumulation of body fat induce important metabolic and endocrine alterations in the organism. Notably, obese humans and animals frequently present reduced GH levels, compared to lean individuals (Rasmussen et al. 1995, Cordido et al. 1996, Luque & Kineman 2006, Luque et al. 2011, Steyn et al. 2013, Roelfsema & Veldhuis 2016, Sanchez-Garrido et al. 2020). BMI (Roelfsema & Veldhuis 2016) and intra-abdominal fat (Vahl et al. 1997) are inversely correlated with GH secretion in healthy adults. Weight loss can restore the pattern of GH secretion in obese subjects (Rasmussen et al. 1995). The causes of the obesity-induced reduction in GH secretion are not totally clear, but it is probably related to the high insulin levels normally exhibited by obese subjects (Luque & Kineman 2006, Steyn et al. 2013, Huang et al. 2021a). The prevention of hyperinsulinemia in obese mice is sufficient to increase pulsatile GH secretion without changes in body weight (Huang et al. 2021a). Plasma FFA is also increased in obesity (Petersen & Shulman 2018), and although an acute reduction in FFA levels does not significantly affect GH secretion in obese patients, GHRH-induced GH secretion is robustly increased when FFA levels are suppressed (Cordido et al. 1996). Thus, both elevated insulin and FFA levels are likely factors that contribute to the obesity-induced suppression of GH secretion.

Since GH stimulates fat mobilization and oxidation, as well as protein anabolism, which in turn can favor energy expenditure by increasing lean body mass, GH administration has been considered as a potential pharmacological treatment of obesity (Mekala & Tritos 2009, Huang et al. 2020). GH treatment in obese individuals modestly reduces fat mass, visceral adiposity, and total and low-density lipoprotein-cholesterol, whereas lean body mass is increased (Mekala & Tritos 2009, Huang et al. 2020). However, slight increases in plasma glucose and insulin levels are also observed in GH-treated patients (Mekala & Tritos 2009, Huang et al. 2020). Thus, according to human studies, the efficacy of the therapeutical use of GH to treat obesity is relatively limited. Conversely, animal studies have shown that strategies that increase GH secretion in obese mice cause fat reduction, associated with increases in lipolysis, lipid oxidation, and energy expenditure, leading to an improved metabolic profile (Huang et al. 2021a,b). Therefore, future studies are still necessary to determine the relationship between changes in GH secretion and the pathophysiology of obesity.

Conclusions

Recent studies have demonstrated that GH-responsive neurons are involved in the organization of physiological responses in situations of metabolic stress (Furigo et al. 2019a,b, 2020, Quaresma et al. 2019, Teixeira et al. 2019, de Lima et al. 2021a,b, Pedroso et al. 2021, Wasinski et al. 2021a). These novel findings, together with the well-known effects of GH increasing fat mobilization, blood glucose levels, and insulin resistance (Devesa et al. 2016, Ranke & Wit 2018, Dehkhoda et al. 2018), represent key adaptations that contribute to restoration of homeostasis during important metabolic challenges. Thus, the ‘growth effect’ of GH represents only one physiological function of this hormone. However, another important role of GH, which is not represented in its name, is to act as a circulating factor that coordinates multiple central and peripheral responses that help the organism overcome periods of metabolic deficits or high energy demands. During these situations, putative conflicting effects of GH (e.g. anabolic vs catabolic effects, or orexigenic vs lipolytic effects) are reconciled into a single major goal that is to increase the chances of survival when the organism is challenged by metabolic stresses.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

The author’s research has been funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP/Brazil grant numbers: 2019/21707-1 to RF; 2020/10102-9 to MRT and 2020/01318-8 to JDJ).

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  • Figure 1

    Summary of the effects of GH in different tissues. These effects can be caused either by direct action of GH or through indirect mechanisms. Direct effects mean that they are mediated by GHR signaling in that tissue. Example of indirect effect is the insulin resistance in the liver and muscle caused by the increased GH-induced lipolysis in the white adipose tissue.

  • Figure 2

    Neuronal populations that are responsive to GH and the described effects of GH receptor signaling in each one. The photomicrographs show neurons expressing pSTAT5 (magenta nuclear staining) after an acute GH stimulus. The cytoplasm of AgRP or POMC neurons is labeled in green. Double-labeled neurons appear as white or are indicated by the arrows. 3V, third ventricle; ARH, arcuate nucleus of the hypothalamus; VMH, ventromedial nucleus of the hypothalamus.

  • Figure 3

    GH can have either synergic or antagonistic effects on insulin, depending on the situation.

  • Figure 4

    Scheme illustrating how GH action in the periphery and CNS coordinates multiple adaptations that help to restore homeostasis during situations of metabolic stress, such as prolonged food restriction, hypoglycemia, exercise, and pregnancy.

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