Neuroendocrine and Metabolic Regulation of Plasma Growth Hormone Secretory Profiles

Abstract

Like many other neuroendocrine hormones, growth hormone (GH; somatotropin) secretion is pulsatile with regular releasing bursts on a relatively low constitutive basal secretion. This chapter discusses current knowledge of the regulation and the function of GH pulsatile profiles, with new development of laboratory approaches and introduces knowledge about GH functions on metabolic regulation in addition to the conventional concept of a role in regulating body growth. As reported in the literature, amplitude, frequency, and regularity of GH secretion are tightly linked to metabolic conditions with clear species and gender differences. In response to negative and positive energy balances, the GH pulsatile pattern changes to mobilize or store energy in adipose, muscle, and liver in order to accommodate the changing nutritional conditions. Changes in GH pulsatility are achieved through regulating the hypothalamo–pituitary GH axis with altered levels of key stimulatory and inhibitory hormones, GH-releasing hormone (GHRH) and somatostatin (SRIF, somatotropin release inhibiting factor). The hypothalamic–pituitary GH axis is constantly under the influence of peripheral metabolic factors, such as lipid and glucose levels; peripheral metabolic regulatory hormones, such as leptin and insulin; and central metabolic regulatory neuropeptides, such as neuropeptide Y and melanocortin. Regulation of the hypothalamic–pituitary GH axis is achieved through activation of cell membrane receptors, intracellular signaling pathways, and membrane ion channels. Detailed regulatory mechanisms are discussed in this chapter in order to understand the coupling of cell electrophysiological properties and the hormone secretory process of exocytosis in hypothalamic neurons and pituitary GH-secreting somatotrophs. Technical advances in electrophysiology, cell imaging analysis, and real-time in vivo hormone analysis are discussed to deepen the understanding of physiological and pathophysiological regulation of GH secretion. Future directions are also discussed, as are unanswered questions in this field.

Full text

Review
Insulin and Growth Hormone Balance:
Implications for Obesity
Zhengxiang Huang,
1
Lili Huang,
1
Michael J. Waters,
2
and Chen Chen
1,
*
Disruption of endocrine hormonal balance (i.e., increased levels of insulin, and
reduced levels of growth hormone, GH) often occurs in pre‐obesity and obesity.
Using distinct intracellular signaling pathways to control cell and body metabo-
lism, GH and insulin also regulate each other’s secretion to maintain overall
metabolic homeostasis. Therefore, a comprehensive understanding of insulin
and GH balance is essential for understanding endocrine hormonal contributions
to energy storage and utilization. In this review we summarize the actions of, and
interactions between, insulin and GH at the cellular level, and highlight the associ-
ation between the insulin/GH ratio and energy metabolism, as well as fat accumu-
lation. Use of the [insulin]:[GH] ratio as a biomarker for predictingthe development
of obesity is proposed.
Insulin–GH balance
Obesity (see Glossary) is a major health issue in the contemporary world and has a strong
association with type 2 diabetes (T2D), cardiovascular disease, and cancer. Hormonal imbalance
often occurs before or during obesity and may play a causal role in the development of obesity
and associated chronic diseases. Insulin and GH, two vital counter-regulatory hormones for glu-
cose and lipid metabolism, are often dysregulated in obesity (increased insulin and reduced GH)
[1], although the cause and consequence of such hormonal imbalance have not been fully clari-
fied. In the evolutionary view, insulin promotes energy storage in the condition of energy surplus,
whereas GH promotes lipid mobilization and oxidation when food is sparse [2]. During natural
selection over the past million years, the human body has evolved an endocrine system adapted
to an environment with insufficient food supply. However, in modern developed societies with
easy food access, overnutrition often occurs. This shifts the dominant role towards insulin
(increased) and away from GH (suppressed) [3,4]. This shift hinders lipid breakdown and pro-
motes further energy storage and lipid synthesis, which exacerbates the development of obesity.
Surprisingly, a comprehensive review of the balance between insulinand GH (insulin–GH balance)
and its physiological significance is lacking. In this review we give a brief summary of the signaling
crosstalk between insulin and GH at the cellular level, and summarize recent findings. We analyze
changes in the insulin–GH balance and the association with energy metabolism in various
physiological and pathophysiological conditions, and we discuss the implications of the insulin–
GH balance in the treatment of obesity.
Physiological Roles of Insulin and GH
Insulin and GH both display pulsatile secretion. Synthesized in pancreatic βcells, peak
secretion of insulin is predominant after each meal with small oscillations throughout the day
[5]. GH is released from somatotrophs in the pituitary gland,anditssecretionpatternis
characterized by low baseline secretion with several dominant pulses at rhythmic intervals
[6]. Although the physiological impact of pulsatile secretion is not fully understood, pulsatility
may contribute to receptor mobilization, turnover, and associated cellular signaling, including
sexual dimorphism [7].
Highlights
Insulin and GH are counter-regulatory
hormones in terms of glucose and lipid
metabolism, but act synergistically in
protein metabolism. They also mutually
regulate the secretion of each other,
forming a complex regulatory network.
The balance between insulin and GH is
associated with substrate and energy
metabolism. In obesity, the hormonal im-
balance (high insulin and low GH) pro-
motes further fat accumulation.
Clinical data from various physiological
and pathophysiological conditions with
insulin and GH changes indicate that
the [insulin]:[GH] ratio correlates nega-
tively with energy expenditure and corre-
lates positively with fat accumulation.
The [insulin]:[GH] ratio may serve as a
biomarker for monitoring and predicting
the development of obesity. Modulation
of insulin–GH balance is a promising tar-
get for managing obesity.
1
School of Biomedical Sciences,
University of Queensland, St Lucia,
Brisbane, Australia
2
Institute for Molecular Bioscience,
University of Queensland, St Lucia,
Brisbane, Australia
*Correspondence:
chen.chen@uq.edu.au (C. Chen).
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© 2020 Elsevier Ltd. All rights reserved.
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TEM 1513 No. of Pages 13

Intracellular Signaling Pathways of Insulin and GH
The classic insulin receptor signaling pathways generally include PI3K/Akt and Ras/MAPK, which
regulate metabolic and mitogenic effects, respectively. Activation of the PI3K/Akt pathway is
dependent on tyrosine phosphorylation of the adaptors insulin receptor substrate 1 and
2 (IRS1/2), whereas Ras/MAPK can also be activated through IRS1/2-independent pathways
[8]. The mammalian target of rapamycin complex 1 (mTORC1), that is activated by Akt, is an
essential component in the regulation of lipid and protein metabolism [8].
The GH receptor is a member of the class I cytokine receptor family. Following GH binding, it
activates the Janus kinase 2 (JAK2)–signal transducer and activator of transcription (STAT) and
Src/MAPK pathways [9], where the former dominantly regulates metabolic effects and the latter
regulates mitogenic function. JAK2 controls metabolic effects by activating STAT1, 3, 5a, and
5b, of which STAT5b is the most prominent and also promotes insulin-like growth factor 1
(IGF-1) production, hence linear growth [10]. Some studies suggest that JAK2 also phosphory-
lates IRS1/2 and activates the PI3K/Akt pathway [11–13]. However, these studies either used
a supraphysiological GH dose [12,13] or did not determine the physiological effects of GH
administration [11], and their conclusions may not apply to a physiological scenario.
Because both insulin and GH regulate lipid/glucose/protein metabolism, their effects and
signaling pathways are further discussed based on target substrate metabolism. We limit
coverage of insulin receptor signaling because this has been thoroughly reviewed [14]. The
actions and signaling pathways of insulin and GH are summarized in Figure 1.
Actions of Insulin and GH Receptor Signaling on Substrate Metabolism
Lipid Metabolism
As a fat-sparing hormone, insulin promotes lipogenesis while inhibiting lipolysis and lipid oxidation
(Figure 1). By contrast, the major effect of GH on lipid metabolism is through inducing lipolysis [2],
which increases free fatty acid (FFA) and glycerol release from adipose tissue into the circulation.
The mechanism of increased lipolysis by GH is not yet fully understood. Some studies suggest
that GH increases the expression and action of β-adrenergic receptors [15,16], which activate
hormone-sensitive lipase (HSL) by increasing the intracellular level of cAMP ([cAMP]i) via activation
of protein kinase A (PKA) [17]. Other studies suggest that GH increases lipolysis through activa-
tion of MEK/ERK and inhibition of PPARγand fat-specific protein 27 (FSP27) [18]. Although
increased circulating FFA levels are associated with metabolic diseases (e.g., non-alcoholic
fatty liver disease and T2D) [19], physiologically increasing GH secretion (e.g., exercise or fasting)
does not lead to such diseases. This paradox can be partially explained by GH-induced lipid
oxidation. GH increases brown adipose tissue (BAT) function and white adipose tissue (WAT)
browning/beiging [16] (discussed later). GH also stimulates lipid uptake in muscle by increasing
the activity of muscle lipoprotein lipase (LPL) [20]. FFA released from WAT is taken up and
oxidized in other tissues, and the net effect of elevated GH therefore promotes reduction of
whole-body fat content. Recent studies have also found that GHR–JAK2–STAT5 signaling in-
hibits lipid uptake and de novo lipogenesis in the liver, partly through inhibition of PPARγand
downstream CD36 [21–24], indicating that GH has a direct effect on hepatic lipid metabolism
and can reduce non-alcoholic fatty liver disease [23].
Glucose Metabolism
Upon food intake, secreted insulin promotes glucose uptake and glycogen synthesis, while
inhibiting gluconeogenesis through the PI3K/Akt pathway (Figure 1). GH stimulates gluconeogen-
esis [2] in the liver, partly through the STAT5 pathway, which includes an increase in phosphoenol-
pyruvate carboxykinase (PEPCK), glucose 6-phosphatase [25], and pyruvate dehydrogenase
Glossary
Acromegaly: a condition in which the
pituitary produces excessive GH during
adulthood, mostly due to a pituitary
adenoma.
Growth hormone (GH) deficiency:
the pituitary is unable to produce
sufficient GH because of primary lesion.
Childhood-onset GH deficiency is mainly
due to genetic defects, whereas adult
GH deficiencycan be caused by multiple
factors including trauma, infections,
tumors, or radiation therapy. Reduced
secretion of GH in obesity does not
belong to this category in this review.
However, it is often referred as 'relative
GH deficiency' in obesity in most
literature.
Insulin-like growth factor 1 (IGF-1):
IGF-1 is produced by a variety of cell
types following GH stimulation.
Circulating IGF-1 is mainly produced by
the liver and acts as a negative regulator
of GH secretion. Local IGF-1 produced
by bone and musclecontributes to linear
growth and protein anabolism.
Obesity: according to the World Health
Organization, obesity is defined as a
body mass index (BMI, body weight in
kg divided by height in m squared) of 30
or more.
Pegvisomant: a drug used for treating
acromegaly in the clinic that blocks
downstream signaling of the GH
receptor. It is a modified version of
human GH that competes with native
GH for the GH receptor and prevents its
activation.
Pituitary gland: an important
endocrine organ located in the brain,
under the h ypothalam us. It res ponds to
hormonalsignals from the hypothalamus
(e.g., GH-releasing hormone) and
produces hormones (e.g., GH) to
regulate body functions.
Sulfonylurea: an antidiabetic drug that
increases insulin secretion by closing
ATP-sensitive potassium channels on
pancreatic βcells.
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kinase 4 (PDK4) gene expression [26]. GH also stimulates glycogenolysis in the liver [27]. A recent
study finds that decreased debranching enzyme (AGL) and increased glycogen branching enzyme
(GBE1) expression are direct STAT5 targets in the liver of mice with disruptedSTAT5 signaling [24],
suggesting an important role for AGL and GBE1 in GH-induced glycogenolysis.
Protein Metabolism
Although insulin and GH have distinct effects on lipid and glucose metabolism, both promote
protein anabolism by increasing protein synthesis and reducing protein breakdown. Further,
both insulin and IGF-1 promote protein anabolism through mTORC1, which is activated by
PI3K/Akt [28].GHhasbeenshowntopromoteproteinsynthesisthroughthesamepathway
[29], but it seems that this effect is mainly through IGF-1 autocrine/paracrine action because
Insulin/IGF-1 receptor
GH receptor
Src
MAPK/
ERK
Ras
PI3K/
Akt
STAT5
IGF-1 SREBP GSK3 FOXO1
mTORC1
Protein
synthesis
↑
PPARγPPARα
UCP1PPARγ CD36 PEPCK/
PDK4 HSL
Proliferaon
Differenaon
Development
Lipid ulizaon ↓
Lipogenesis ↑
Lipolysis ↓
Glycogen synthesis ↑
Gluconeogenesis ↓
GLUT4 translocaon ↑
JAK2
PPARγ
β-adrenergic
receptors
[cAMP]
↑
HSL
Lipolysis ↑
Lipogenesis ↓
IRS
Insulin
[cAMP]
↓
IGF-1
GH
Lipogenesis ↓
TG uptake (liver) ↓
Brown/beige fat funcon ↑
Gluconeogenesis ↑
Glycogenolysis ↑
AGL
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Figure 1. Signaling Pathways and Their Effectson Substrate Metabolism of Insulin and Growth Hormone(GH)
Receptors. The major signaling pathways downstream of the insulin receptor are PI3K/Akt and Ras/MAPK,and the primary
signaling pathways of the GH receptor are JAK2/STAT and Src/MAPK. While PI3K/Akt and JAK2/STAT pathways contribute
to the metabolic effects of insulin and GH receptor signaling, the MAPK pathway is responsible for mitogenic effects. The
distinct effects in glucose and lipid metabolism of insulin and GH are shown in yellow and red, respectively. The synergistic
effects of insulin and GH are shown in green. The dashed line indicates that the physiological effects of JAK2-PI3K/Akt
pathway are not clear. Abbreviations: AGL, glycogen debranching enzyme; FOXO1, Forkhead Box O1; GLUT4, glucose
transporter type 4; GNG, gluconeogenesis; GSK3, glycogen synthase kinase 3; HSL, hormone-sensitive lipase; IRS,
insulin receptor substrate; JAK2, Janus kinase 2; mTORC1, mammalian target of rapamycin complex 1; PDK4, pyruvate
dehydrogenase k inase 4; PEPCK, phosphoenolpyruvate carboxykinase; PI3K/Akt, p hosphatidylin ositol 3-kinase/protein
kinase B; PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element-binding protein; STAT,
signal transducer and activator of transcription; TG, triglyceride; UCP1, uncoupling protein 1.
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GH administration increases muscle mass in wild-type mice but not in mice lacking the IGF-1 re-
ceptor specifically in muscle [30]. In addition, GH increases lipolysis and FFA levels in stress states
(such as fasting and exercise), thus reducing protein usage and exerting a protein-sparing effect [31].
Interactions between Insulin and GH
Molecular and Cellular Effects
Although exerting similar effects on protein metabolism, insulin and GH show opposite effects
on glucose and lipid metabolism. As discussed earlier, insulin reduces blood glucose and
promotes lipogenesis, whereas GH increases blood glucose and facilitates lipolysis and lipid
oxidation. This antagonism is further evidenced by insulin resistance following GH administra-
tion or in acromegaly patients [32]; downregulation of GH receptor signaling is found in vitro
following insulin pretreatment [33]. In addition to opposing effects on the same gene target
(e.g., insulin inhibits HSL, whereas GH activates HSL), GH antagonizes insulin action through
post-receptor signaling pathways. Further, the insulin sensitivity seen in GH receptor-deleted
mice is partly a consequence of the removal of suppression of insulin-sensitizing hormones
such as adiponectin, FGF1, and IL-15 [24].
At the post-receptor level, GH transgenic mice show decreased insulin receptor levels and
decreased insulin-stimulated phosphorylation of crucial molecules in the insulin receptor
pathway, including insulin receptor, IRS1/2, and PI3K [34]. In addition, GH induces p85α
subunit, a regulatory subunit of PI3K [35], and thus inhibits PI3K activity via p110 catalytic
subunit inhibition [35] as well as by phosphatase and tensin homolog (PTEN) activation [36]. GH
also activates suppressor of cytokine signaling (SOCS) 1 and3, leading to insulin signaling inhibition
[37]. These findings demonstrate the antagonizing effect of GH on insulin action at the cellular level.
Further, although physiological insulin is necessary for the maintenance of surface GH receptors,
chronic high insulin levels reduce surface GH receptor availability [38] and GH-induced phosphor-
ylation of JAK2 and STAT5b in vitro [34], indicating that hyperinsulinemia may lead to GH resis-
tance. The intracellular interactions between insulin and GH are summarized in Figure 2.
Reciprocal Regulation of Secretion
The regulation of GH secretion by insulin is complex. An acute increase in insulin levels by exog-
enous injection, which depresses blood glucose levels below the normal range, stimulates GH
secretion. This is seen in the insulin tolerance test (Figure 3A), a widely accepted method for eval-
uating GH secretion capacity in adults [39]. However, there is no evidence that a physiological
increase in insulin levels (i.e., glucose-stimulated insulin secretion, GSIS) (Figure 3B) influences
GH secretion. Conversely, chronic hyperinsulinemia, that is often seen in obesity and T2D
(Figure 3C), can directly reduce GH secretion in somatotrophs independently of IGF-1 signaling
[40]. In addition, hyperinsulinemia reduces IGFBP-1 production in the liver [41], which in-
creases circulating free IGF-1 and thus inhibits GH secretion by IGF-1 negative feedback on
the pituitary gland. Conversely, low insulin levels often lead to increased GH secretion. This is
mainly due to reduced surface expression of the GH receptor in the liver [38], leading to re-
duced IGF-1 production, which diminishes the IGF-1 negative feedback on the pituitary
gland. This is often observed in type 1 diabetes (T1D) patients and in the fasting state in
humans (Figure 3D,E).
Likewise, the regulation of insulin secretion by GH is also sophisticated. High levels of circulat-
ing GH in acromegaly patients (Figure 3F) cause hyperinsulinemia because of the insulin-
antagonistic effect of GH, discussed above. Low GH levels in the short term, as seen in
childhood-onset growth hormone deficiency adolescents (Figure 3G), increase insulin sen-
sitivity [42], probably due to the removal of the insulin-antagonistic effect of GH. In the long
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term, adult GH-deficient patients (Figure 3H) show similar fasting hyperinsulinemia to body
mass index (BMI)-matched obese individuals, probably due to insulin resistance [43] caused
by reduced fat breakdown and increased fat mass. Apart from distinct insulin sensitivity in
short- and long-term GH deficiency, it is generally acknowledged that GH is required for pan-
creatic βcell proliferation [44]. Thus, children with isolated-GH deficiency are often reported to
have reduced βcell function [45].
The Ratio of Circulating Insulin to GH Correlates with Energy Expenditure and Fat
Accumulation
The overall analysis of insulin and GH in various physiological and pathophysiological conditions
(Table 1) supports the use of the ratio of circulating insulin to GH ([insulin]:[GH] ratio) to reflect en-
ergy metabolism. To be specific, the higher the [insulin]:[GH] ratio, the lower the energy expendi-
ture, the more fat accumulation, and vice versa. Details are discussed in the following sections.
Although analysis of insulin in both postabsorptive and postprandial states as a function of pulsa-
tile GH components (i.e., pulsatile, basal, GH mass per pulse) may provide a more comprehen-
sive and more in-depth understanding of the role of the hormone properties, it should be noted
that the overall levels of insulin and GH mentioned here are restricted to fasting insulin and total
GH secretion, respectively, owing to the limited number of parameters assessed in most studies.
Conditions with Decreased [Insulin]:[GH] Ratio
Reduced [insulin]:[GH] ratio is found in T1D patients [46], individuals performing aerobic exercise
[47,48], and acromegaly patients, who have ~10-fold increased basal GH secretion [49,50] with a
compensatory twofold increase in fasting insulin level [49](Table 1, upper panel). As expected,
Insulin receptor
GH receptor
IRS
PI3K
STAT5
JAK2
SOCSs
p110
p85
PTEN
JAK2
IRS
GH
Insulin
?
?
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Figure 2. Intracellular Interaction between Insulin and Growth Hormone (GH). Downstream signaling by the insulin
receptor (yellow) and the GH receptor (red) antagonizes each other at the cellular level through various pathways. The
question mark indicates an unknown mechanism. Abbreviations: PTEN, phosphatase and tensin homolog; SOCS,
suppressor of cytokine signaling.
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T1D patients [51,52], regularly exercised individuals [53], and acromegaly patients [50,54] show
decreased fat mass compared with body weight-matched controls. In terms of energy
expenditure, studies show that T1D patients have increased basal energy expenditure both
untreated and after the withdrawal of insulin treatment [55,56]. Exercising individuals show higher
basal metabolic rate both in self-comparison trials [57,58] and relative to non-exercise individuals
[59]. Several studies also show that acromegaly patients have increased energy expenditure
[49,50,54,60,61]. Therefore, reduced [insulin]:[GH] ratio seems to be associated with reduced
Table 1. Changes in Energy Expenditure and Fat Mass in Different Diseases/Conditions with Increased or
Decreased [Insulin]:[GH] Ratio
Condition Insulin GH Energy
expenditure
Fat
mass
Refs
Decreased [insulin]:
[GH] ratio
T1D ↓↑↑ ↓[46,51,52,55,56]
Exercise ↓↑↑ ↓[47,48,53,57–59]
Acromegaly ↑↑↑↑ ↓[49,50,54,60,61]
Increased [insulin]:
[GH] ratio
AGHD ↑↓↔or ↓↑[43,73,80]
Sleep
disorders
↑or
↔
↓↓ ↑ [64,65,67,69,70,75–78,82]
Aging ↑or
↔
↓↓ ↑ [62,68,71,72]
Obese
PCOS
↑↓↓ ↑[63,66,74,79]
Simple
obesity
↑↓↓ ↑[83]
High insulin
Low insulin
(T1D)
Insulin
GHR on liver ↓ IGF-1 ↓
GH
High GH
(acromegaly)
Low GH
(GHD)
Glucose ↓
Acute
Chronic
(obesity)
Insulin resistance
(ITT)
GSIS doesn't
change GH
(GSIS)
Pancreac
β cells
Somatotrophs
Increased fat mass
Insulin resistance
Childhood
Adult
+
-
-
+
+
Conditions Primary
change
Secondary
change
(A)
ITT Insulin ↑ GH ↑
(B)
GSIS Insulin ↑ GH ↔
(C) Obesity or T2D
Insulin ↑ GH ↓
(D)
T1D Insulin ↓ GH ↑
(E)
Fasting Insulin ↓ GH ↑
(F)
Acromegaly GH ↑↑ Insulin ↑
(G) Childhood GHD
GH ↓ Insulin ↓
(H) Adult GHD GH ↓ Insulin ↑
+
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Figure 3. Inter-regulation between Insulin and Growth Hormone (GH). Primary increase in insulin secretion leads to either increased (A), unchanged (B), or
decreased (C) GH secretion, according to the conditions. Primary decrease in insulin secretion leads to increased GH secretion (D,E). Primary increase in GH secretion
leads to increased insulin secretion by compensation (F), whereas primary decrease in GH secretion (i.e., GH deficiency) leads to either decreased (G) or increased (H)
insulin secretion as a function of onset age. Examples of diseases/conditions for changed insulin or GH secretion are indicated in the brackets and table. Symbols and
abbreviations: ↑, increase; ↓, decrease; ↔, no change; GHD, growth hormone deficiency; GHR, growth hormone receptor; GSIS, glucose-stimulated insulin secretion;
ITT, insulin tolerance test, a widely accepted method for evaluating GH secretion capacity in humans; T1D/T2D, type 1 and 2 diabetes.
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fat mass and increased energy expenditure, at least in untreated T1D patients, regularly exercised
individuals, and acromegaly patients.
Conditions with Increased [Insulin]:[GH] Ratio
Increased [insulin]:[GH] ratio is usually seen in conditions of adult GH deficiency (AGHD), aging,
obese polycystic ovary syndrome (PCOS), and sleep disorders such as sleep deprivation and ob-
structive sleep apnea (OSA) (Table 1, lower panel). All show a profound reduction of GH [62–65],
but with different changes in insulin secretion (elevated in AGHD [43], obese PCOS [66], OSA [67],
and in some aging individuals [68], whereas this is unaltered in sleep deprivation [69,70] and other
aging individuals [71]). Expectedly, aging is accompanied with reduced energy expenditure and
increased fat mass [72]. AGHD [73] and obese PCOS [74] patients have increased fat mass com-
pared with age-, sex-, height-, and weight-matched healthy adults, whereas both sleep depriva-
tion and OSA patients have a strong correlation with obesity [75] and show reduced ability to lose
weight following lifestyle intervention [76–78]. In terms of energy expenditure, obese PCOS
patients have reduced postprandial thermogenesis [79]. Although studies show no significant
changes in the energy expenditure of AGHD patients compared with body weight-matched
obese individuals [73,80], this is likely due to adaptation of energy intake and expenditure after
long-term GH deficiency. At the onset of the GH deficiency, patients may have reduced energy
expenditure, as shown in a mouse model of adult-onset, isolated GH deficiency [81]. In sleep dis-
orders, one study shows that acute sleep deprivation reduces both resting and postprandial en-
ergy expenditure [82]; others show increased energy expenditure, which is likely to be a result of
more awake hours during the night and increased food intake [75].
Simple obesity is also a condition in which hyperinsulinemia is accompanied by low GH secretion
[83], as well as increased fat mass. However, it is difficult to determine energy expenditure accu-
rately because of the lack of proper controls. It would be important to look at the energy expen-
diture difference between obese and non-obese individuals with matched muscle mass because
muscle is the major organ that contributes to energy expenditure in humans. Nevertheless,
because of the high body weight and fat percentage in obese individuals, it is speculated that
these individuals may have reduced energy expenditure and increased fat accumulation.
Although insulinoma patients show increased insulin secretion, neither GH secretion nor energy
expenditure has been studied in this rare disease. Other diseases with reduced GH secretion
or action (e.g., childhood-onset GH deficiency, Turner syndrome, and Laron syndrome) are not
discussed because the significantly reduced height of these patients results in a lack of height-
and body weight-matched healthy controls.
Disease Therapies That Directly Modify Insulin or GH Levels
In addition to the changes in endogenous insulin/GH discussed above, alterations in the circulat-
ing levels of insulin/GH seen in diseased individuals following pharmacological or surgical inter-
vention also support application of the [insulin]:[GH] ratio to energy expenditure and fat
accumulation. Following long-term insulin or sulfonylurea treatment, the [insulin]:[GH] ratio of
T2D patients tends to be increased, followed by a reduction in resting metabolic rate [84]or
total energy expenditure [85]. The high basal energy expenditure of T1D patients returns to
normal following insulin administration [55], with a concurrent increase in the [insulin]:[GH] ratio.
Increased insulin levels as a result of either insulin or sulfonylurea treatment in T2D [86], as well
asinsulininjectioninT1D[87], lead to increased fat mass. In terms of changes in GH levels,
GH-deficient patients show increased energy expenditure [80,88] and decreased fat accumula-
tion [88] after GH treatment compared with pretreatment. On the other hand, following reduction
of excessive GH secretion by surgical removal of a GH-releasing tumor, which is expected to
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increase the [insulin]:[GH] ratio, acromegaly patients show reduced energy expenditure and basal
metabolic rate [50], and display a tendency to weight-gain [89].
Evidence from Mouse Models
Similar to the above mentioned studies in humans, rodent studies also support the association be-
tween the [insulin]:[GH] ratio and energy metabolism. Reduction of Ins1 expression in an Ins2 null
background leads to increased energy expenditure and resistance to diet-induced obesity when
fed with a high-fat diet [90]. Although GH levels were not measured in this model, they are expected
to increase because of attenuation of hyperinsulinemia, leading to a reduced [insulin]:[GH] ratio. The
[insulin]:[GH] ratio is increased in adult-onset GH deficiency in mice, followed by reduced energy
expenditure and increased fat mass [81]. With bovine (b)GH overexpression, bGH mice have
N400-fold higher GH levels [91] and ~10-fold higher insulin levels [92] compared with wild-type lit-
termates, thus displaying a decreased [insulin]:[GH] ratio. Similarly to acromegaly patients, these
mice show both increased energy expenditure and decreased fat percentage [92]. A recent
study shows that sodium/glucose cotransporter 2 inhibitor (SGLT2i) treatment reduces
hyperinsulinemia and restores GH secretion in an obese mouse model through inhibition of glucose
reabsorption in the kidney [93], leading to a reduced [insulin]:[GH] ratio. The hormonal changes
contribute to improved insulin sensitivity, increased lipid usage, and reduced fat accumulation [93].
To summarize, various physiological and pathophysiological conditions support a negative
correlation between [insulin]:[GH] ratio and energy expenditure, and a positive correlation with
fat accumulation. Changes in this balance may lead to improvement or deterioration of the
metabolic conditions.
Potential Mechanisms of Insulin–GH Balance in Regulating Energy Expenditure
Apart from the effects of different [insulin]:[GH] ratios in various diseases/treatments on energy
expenditure, some clinical studies show that blocking GH receptor signaling by pegvisomant
reduces basal energy expenditure in healthy individuals [94], acromegaly patients [95], and
insulin-resistant non-diabetic men [96]. These results suggest a direct effect of GH on energy
expenditure. The mechanisms behind the changes in energy expenditure as a function of the
[insulin]:[GH] ratio may be associated with alterations of mitochondrial function, BAT function,
and WAT browning by either insulin or GH.
Mitochondria are the primary site of energy production in the cell. The effects of insulin on mito-
chondria seem to depend on overall insulin sensitivity. Reduced mitochondria function is seen
in insulin-resistant T2D patients [97] and in mice with disruption of insulin receptor signaling
[98], whereas increased mitochondrial function is observed in healthy individuals with acute
insulin infusion [97]. Unlike insulin, acute GH administration increased mitochondrial function
and gene expression in both lean and obese humans [99,100]. Moreover, a GH-deficient
model (spontaneous dwarf rat) shows decreased mitochondrial area in hepatocytes [101], and
GH supplementation increases mitochondria number in these isolated hepatocytes [102].
Although one study indicates that GH can accumulate in the mitochondria after acute GH administra-
tion, and inhibits mitochondrial function in isolated mitochondria [103], this study is limited to isolated
mitochondria, and may not reflect the overall cell-based mechanisms. Therefore, the overall effect of
GH seems to increase mitochondrial function, but the exact mechanism remains unclear.
BAT and browning WAT are also essential contributors to energy expenditure. It has been shown
that JAK2 is crucial for the induction of UCP1 in BAT in response to cold exposure, high-fat diet
feeding, and adrenergic stimulation [104]. GH treatment increases UCP1, 2 and 3 expression in
BAT and WAT of obese KK-Ay mice [105]. In vitro study shows that GH treatment increases
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UCP1 expression in 3T3-L1 cells [106]. A recent animal study reveals that GH receptor signaling
is necessary for the induction of beige fat through STAT5 induction of ADRB3 [16]. In addition, GH
also supports beige fat by increasing both circulating and local adipose tissue production of
FGF21 [16]. However, some studies in mouse models with reduced GH secretion show enlarged
BAT or increased BAT function [107]. The reason is unknown, although it may relate to the smaller
size of these mice, hence increased cold stress. On the other hand, hyperinsulinemia reduces
BAT markers as well as mitochondrial content and activity in vitro and in vivo [108]. In high-fat-
fed mice, reducing hyperinsulinemia by reducing βcell insulin gene dosage leads to increased en-
ergy expenditure and UCP1 expression in WAT [90]. These results indicate that GH may increase
the thermogenic function of BAT and WAT browning, thus increasing energy expenditure,
whereas hyperinsulinemia has the opposite effect.
Treatment of Obesity by Modulating Insulin or GH
Acknowledging the effects of insulin–GH balance on substrate and energy metabolism, it is likely
that modifying insulin or GH levels could be a useful therapeutic approach to treat obesity.
Although no drug is currently approved to treat obesity by directly targeting the insulin/GH
balance, there are several clinical studies with promising outcomes. We review here clinical
studies that directly reduce insulin (diazoxide) or increase GH [recombinant human GH (rhGH)
and tesamorelin], and summarize the pros and cons of these treatments (Table 2).
Table 2. Trials of Diazoxide and rhGH Therapy in Obesity
Individuals BMI Dose Duration Fasting
insulin
Oral glucose-
tolerance test
(OGTT) insulin
Fat
mass
Fasting
blood
glucose
(FBG)
Glucose
in OGTT
Insulin
resistance
Other Refs
Diazoxide
24 obese
adults
~40 2 mg/kg/day,
tid
a
(maximum
200 mg/day)
8 weeks ↓↓ ↓↔↔↔ With low-
calorie diet
[110]
35 obese
adults
~42 2 mg/kg/day,
tid (maximum
200 mg/day)
8 weeks ↔↓ ↔↔ ↑ Baseline
insulin does
not match
between
treatment and
placebo group
[112]
18 obese
men
34 50–300 mg
tid
6 months ↓↓ ↓↑ ↑ ↓ With lifestyle
intervention
[111]
44 obese
men
~35 100–350 mg
bid
a
6 months ↓↓ ↓↑ ↑ ↓ With lifestyle
intervention
[109]
rhGH
50 obese
women
35 1.7 ± 0.1
mg/day
(mean dose)
6 months ↓↑ ↑ [116]
62 obese
men
37 1.1 ± 0.08
mg/day
(final dose)
6 months ↓↔ ↔ ↔ Improve
mitochondrial
function
[100]
15 obese
adults
38 0.49 ± 0.07
mg/day
(final dose)
6 weeks ↓↔ ↔ ↔ Decrease
adipocyte size
[117]
50 obese
women
34 1.3 ± 0.5
mg/day
(mean dose)
3 months ↓↑↑ [118]
a
Abbreviations: bid, twice per day; tid, three times per day.
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Treatment of Obesity by Reducing Insulin
Diazoxide inhibits insulin secretion by opening ATP-sensitive potassium (K
ATP
) channels on the
pancreatic βcells. It may recover the suppressed GH secretion in obese individuals through
reducing hyperinsulinemia, thus lowering the [insulin]:[GH] ratio, although this needs to be
confirmed.
Clinical trials of diazoxide (Table 2) show mixed results in terms of glucose and lipid metabolism;
three studies showed reduced fat mass with or without slightly impaired glucose metabolism
[109–111], and one showed no change in fat mass [112]. Importantly, no study has reported
any loss of lean mass during diazoxide treatment. The preservation of lean mass may be associated
with recovery of impaired GH secretion. Interestingly, treating obese children with hypothalamic/
pituitary lesions with diazoxide fails to achieve body weight reduction [113]. This could be due to
inability to recover GH, and thus strengthens the importance of GH in combating obesity. To
summarize, diazoxide treatment shows a significant effect in reducing fat mass and improving
insulin sensitivity in most clinical trials, at the cost of slightly impaired glucose tolerance.
Treatment of Obesity by Increasing GH
The rhGH and tesamorelin treatments to increase GH levels in obesity have been thoroughly
reviewed by Berryman et al. [83] which includes clinical trials from 1967 to 2013. We summarize
the relevant parameters in additional studies after 2013 in Table 2. The overall conclusion is that
rhGH treatment reduces fat mass, increases lean mass, does not change body weight, and may
cause slightly impaired glucose metabolism in the short term.
However, although clinical trials show a promising benefit of GH in treating obesity, there
remain many limitations relating to mimicking a physiological equivalent GH pattern. rhGH
injection induces a large plateau for ~4–8 h, which is different from the physiological pulsatile
secretion in which there are low levels of basal secretion and large secretory pulses at rhythmic
intervals [6]. This may result in different effects on substrate and energy metabolism, given that
pulsatile and continuous GH have different effects on GH receptor and STAT5 activation [7].
Tesamorelin is a GH-releasing hormone (GHRH) analog that has been used to treat HIV-
associated lipodystrophy. It increases GH secretion while preserving the pulsatile secretion
pattern of GH [114]. Clinical trials show that tesamorelin significantly reduces fat mass in obese
individuals without compromising glucose metabolism [83,115]. Although this is encouraging,
the long-term effects on obesity and the cost will need to be considered.
To summarize, rhGH injection significantly reduces fat mass at the cost of slightly impaired glucose
metabolism, whereas tesamorelin shows fat-reducing effects but has little influence on glucose
metabolism. We encourage the further development of lower-cost drugs that can increase pulsatile
GH secretion. These may exert fat mass reduction without impairing glucose metabolism.
Concluding Remarks and Future Perspectives
To summarize, from an evolutionary standpoint, insulin promotes energy storage when food is
plentiful, whereas GH promotes lipid usage to protect proteinwhen food is sparse. In the contem-
porary world with excess food supply, the [insulin]:[GH] ratio increases and is related to an in-
crease in obesity. Given their synergetic effects on protein preservation, and their opposing
effects on glucose and lipid metabolism, as well as their reciprocal regulation of each other’s se-
cretion, insulin and GH should always be investigated concurrently to understand the complex
hormonal network in obesity. From analysis of the [insulin]:[GH] ratio in conditions of physiological,
pathophysiological, and pharmacological challenge, we conclude that the [insulin]:[GH] ratio is
negatively correlated with energy expenditure and is positively correlated with fat accumulation.
Outstanding Questions
What are the molecular mechanisms
by which the insulin–GH balance regu-
lates energy expenditure?
Is hyperinsulinemia the dominant
factor that causes reduced GH secre-
tion in obesity?
To apply the ratio of insulin to GH in the
clinic, it is crucial to define the way in
which insulin and GH levels are col-
lected. Although fasting insulin is
widely accepted for the basal state in-
sulin level, GH measurement is difficult
because of its pulsatile secretion pat-
tern. Is total IGF-1 a suitable surrogate
marker for the 'biologically effective'
GH?
What is the effect of different patterns
of GH (e.g., physiological pulsatile
pattern and 'plateau pattern' by rhGH
injection) on glucose, lipid, and energy
metabolism? Is there a way to supple-
ment GH in a specificpatternwhich
retains fat-reducing effect but mini-
mizes the negative effect on glucose
metabolism?
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10 Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx

In addition, some clinical trials using pharmacological approaches to reduce insulin or increase
GH levels show beneficial effects on obesity.
Therefore, the [insulin]:[GH] ratio could be a potential biomarker for predicting energy expenditure
and the development of obesity in clinical practice. Although fasting insulin is widely accepted as
an indicator of basal state insulin level, the choice of a suitable indicator for GH needs further
study. Random and stimulated GH are commonly used in the clinic. However, they have limited
physiological meaning because of the pulsatile secretion pattern of GH. Measuring the 24 h
secretion profile of GH is the gold standard, but is a complex sampling process and difficult
to use clinically. Therefore, it is crucial to find a surrogate marker to show the 'biologically effective'
GH. Total IGF-1 may be a potential marker, together with N-terminal pro-peptide of type
3 collagen, as used by World Anti-Doping Agency (WADA) for human GH testing in sport.
Whether this is strongly correlated with pulsatile or total or basal GH secretion needs to
be tested in individuals without acromegaly or GH deficiency.
There are still many unknowns in the mechanism of the regulation and effects of insulin and GH,
including the mechanisms underlying reduced GH secretion in obesity and the different effects of
physiological (pulsatile) or therapeutic rhGH injection on substrate and energy metabolism.
Further basic studies will be necessary to answer these questions (see Outstanding Questions).
Acknowledgments
Z.H. is the recipient of a China Scholarship Council PhD scholarship and a University of Queensland international PhD scholarship.
This work is supported by Grants to C.C. from NHMRC and University of Queensland.
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