✕
Journal of Obesity & Metabolic Syndrome

Search

Article

J Obes Metab Syndr 2024; 33(4): 302-313

Published online December 30, 2024 https://doi.org/10.7570/jomes24032

Copyright © Korean Society for the Study of Obesity.

Growth Hormone, Hypothalamic Inflammation, and Aging

Licio A. Velloso1,2, Jose Donato Jr.3,*

Author Affiliations

1Laboratory of Cell Signalling‑Obesity and Comorbidities Research Center, University of Campinas, Campinas; 2National Institute of Science and Technology on Neuroimmunomodulation, Campinas; 3Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil

Correspondence to:
Jose Donato Jr.
https://orcid.org/0000-0002-4166-7608
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo 05508-000, Brazil
Tel: +55-11-3091-0929
Fax: +55-11-3091-7285
E-mail: jdonato@icb.usp.br

Received: September 19, 2024; Reviewed : September 26, 2024; Accepted: November 19, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Go to

While inflammation is a crucial response in injury repair and tissue regeneration, chronic inflammation is a prevalent feature in various chronic, non-communicable diseases such as obesity, diabetes, and cancer and in cardiovascular and neurodegenerative diseases. Long-term inflammation considerably affects disease prevalence, quality of life, and longevity. Our research indicates that the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is a pivotal regulator of inflammation in some tissues, including the hypothalamus, which is a key player in systemic metabolism regulation. Moreover, the GH/IGF-1 axis is strongly linked to longevity, as GH- or GH receptor-deficient mice live approximately twice as long as wild-type animals and exhibit protection against aging-induced inflammation. Conversely, GH excess leads to increased neuroinflammation and reduced longevity. Our review studies the associations between the GH/IGF-1 axis, inflammation, and aging, with a particular focus on evidence suggesting that GH receptor signaling directly induces hypothalamic inflammation. This finding underscores the significant impact of changes in the GH axis on metabolism and on the predisposition to chronic, non-communicable diseases.

Keywords: Chronic disease, Cytokines, Growth hormone, Insulin-like growth factor I, Neuroinflammatory diseases, Obesity

INTRODUCTION

Go to

During the last century, humanity has experienced the historically most significant advancement in socioeconomic standards, science, medicine, lifestyle, technology, and many other areas directly impacting life. One of the consequences of this revolution is that worldwide human longevity has increased from 32 years in 1900 to 77 years in 2020 (www.cdc.gov). While living longer is regarded as a positive aspect of modernity, it is closely linked with the increased prevalence of several chronic, non-communicable diseases such as cancer, cardiovascular diseases, neurodegenerative diseases, diabetes, obesity, and hypertension (Fig. 1). These are all multifactorial conditions that can appear at any time during a lifetime; however, after the age of 60 years, their prevalence undergoes a sharp increase, which places them among the greatest causes of death in the world. Due to their multifactorial nature, no single factor explains or connects these health conditions; however, inflammation permeates all these diseases in different ways, generating great interest regarding its involvement in the pathophysiology of these diseases and its potential as a therapeutic target (Fig. 1).1

Inflammation is a response to distinct challenges to body homeostasis, such as tissue damage, cellular stress, and infections. Inflammatory signals, which include factors such as chemokines, cytokines, biogenic amines, and eicosanoids induce multiple changes in biological processes, resulting in the abnormal regulation of local vascular tonus and permeability, alterations of local or whole-body temperature, edema, and pain, the clinical hallmarks of inflammation.1 The biological purpose of inflammation is to restore cellular, organic, or systemic function when standard homeostatic systems fail. If inflammation cannot acutely restore function or if the mechanisms behind the damage are not controlled and become chronic, there is a risk that inflammation also becomes chronic, adding further complexity to the progression of related disease.2

Several factors play important and determining roles in the inflammatory process. Inflammation begins when immune cells detect potentially harmful signals, such as the presence of a pathogen or the occurrence of tissue injury. Immune cells have receptors that are activated in response to molecular patterns present in pathogens (pathogen-associated molecular patterns [PAMPs]) and in damaged cells (danger-associated molecular patterns [DAMPs]).3 Upon engagement of receptors with DAMPs and PAMPs, intracellular signaling pathways orchestrate a transcriptional program aimed at inducing the expression of key inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and monocyte chemoattractant protein-1, which compose the canonical tetrad of pro-inflammatory cytokines, and chemokines that coordinate the recruitment of other immune cells to the anatomical site under threat.4

Both genetic and environmental factors are involved in the regulation of inflammatory responses. One such environmental factor that plays an essential role in this context is food (Fig. 1). Studies performed over the last 30 years have identified specific nutrients with potent proinflammatory actions; moreover, the mechanisms by which nutrients activate inflammation and how they impact chronic, non-communicable disease progression have been characterized.5 Due to the focus of this review, emphasis will be given to metabolic inflammation, which affects the pathophysiology of obesity and several of its comorbidities.

RELATIONSHIP OF INCREASED INFLAMMATION WITH METABOLIC DISEASES

Go to

In 1993, Hotamisligil et al.6 provided one of the most significant advances in understanding the mechanisms linking obesity and insulin resistance. Studying the adipose tissue of rodents, they demonstrated that mice and rats with obesity and diabetes expressed TNF-α in the adipose tissue, which did not occur in lean mice without diabetes. In addition, they showed that systemically injected TNF-α promoted glucose intolerance due to insulin resistance.6 It was proposed that the hypertrophic adipose tissue was acting as a chronically damaged tissue, which triggered an inflammatory response in an attempt to restore physiological parameters.

Thirty years after the first description of metabolic-associated inflammation, it is known to be a multifactorial process that depends on environmental and genetic factors and can promote damage in distinct tissues and organs. Nutritional factors are important triggers of the process, particularly the consumption of large amounts of saturated fats, which can act by different mechanisms (Fig. 1).7

In animal models, consuming large amounts of saturated fats promotes the rapid activation of an inflammatory response in the hypothalamus, damaging neurons that play a central role in controlling food intake and energy expenditure.8 As neurons are rapidly affected, mice lose the capacity to properly balance food intake and energy expenditure, which accelerates body mass gain and deteriorates systemic metabolism.9

The gut microbiota is also rapidly affected by the consumption of energy-dense foods, particularly those that are poor in fiber and subproducts of fermentation and rich in fats and sugar.10 The major outcomes of this process are related to a reduction of microbial diversity, increased prevalence of microorganisms that promote greater energy harvesting from food, and increased prevalence of microorganisms that disrupt the gut barrier.11 Taken together, these abnormalities favor a positive energy balance and an increase of the transposition of gut lipopolysaccharide to the bloodstream, boosting systemic metabolic inflammation (Fig. 1).5

Dietary fats also affect adipocytes and adipose tissue-resident macrophages, inducing the expression of inflammatory cytokines and chemokines.12 At least in part, this process depends on the capacity of long-chain saturated fats to activate toll-like receptor 4 in bone marrow-derived cells and on the recruitment of systemic monocytes to the adipose tissue.13 These effects are not immediate and depend on long-term consumption of a high-fat diet plus an increase in the mass of adipose tissue, which is different from the rapid effects of saturated fats on the hypothalamus and the gut microbiota.14

The effects of surplus dietary fats on the hypothalamus, the gut microbiota, and adipose tissue are central to metabolic inflammation (Fig. 1).5,9,15 However, there are several other outcomes resulting from the chronicity of this phenomenon, including predisposing the liver to metabolic-associated fatty liver disease, atherosclerosis, Alzheimer’s disease, and some types of cancer. Details regarding the impact of metabolic inflammation on these conditions are out of the scope of this article, and readers interested in these themes are encouraged to read the following authoritative reviews.15-18 Here, we discuss the potential role of the growth hormone (GH) axis in regulating inflammation, metabolism, predisposition to chronic, non-communicable diseases, and longevity.

GH ACTION IN THE BRAIN MODULATES MULTIPLE METABOLIC AND COGNITIVE FUNCTIONS

Go to

Numerous brain regions express the GH receptor (GHR).19-21 Although some studies suggest the presence of local GH production in some areas of the central nervous system (CNS),22,23 pituitary-derived GH is probably the primary source in the brain since GH readily crosses the blood-brain barrier.24,25 GHR signaling recruits signal transducer and activator of transcription 5 (STAT5) as its major intracellular signaling pathway.26 Thus, immunoreactivity against phosphorylated STAT5 (pSTAT5) after an acute GH injection has been frequently used as a marker for GHR-expressing cells in the CNS.19,27,28 Notably, a systemic GH injection induces pSTAT5 in several neuronal populations of the hypothalamus, amygdala, hippocampus, and brainstem.19 Despite the robust responsiveness to GH in the brain, many previous studies focused on the potential role of insulin-like growth factor 1 (IGF-1) to convey the effects induced by changes in GH secretion,29,30 since GH secretion controls hepatic IGF-1 expression and serum IGF-1 level (Fig. 2).31 Thus, separating the direct effects induced by GH on the CNS from the indirect effects mediated by IGF-1 has been challenging.

In recent years, several studies have established the critical role of GHR signaling in the CNS in regulating metabolism.32 A central GH infusion stimulates food intake in mice.33 Furthermore, GH overexpression causes hyperphagia in mice or fish and induces obesity.34,35 GHR ablation in neurons reduces pregnancy-induced hyperphagia.36 GHR signaling in glutamatergic or proopiomelanocortin-expressing neurons blunts the glucopenia-induced hyperphagia.37,38 GHR inactivation in neurons or blockade of ghrelin-induced GH secretion completely abrogates the orexigenic response to ghrelin.39,40 Thus, GH acts in the CNS to stimulate hunger, and this effect is required for the ghrelin orexigenic response. Considering that body and tissue growth are energy-demanding processes, the association between growth and the orexigenic effect of GH makes sense from a physiological perspective.

GHR expression is found in approximately 95% of agouti-related protein (AgRP)-expressing neurons.33 GHR ablation in AgRP neurons prevents key energy-saving adaptations during chronic food restriction, including suppression of the thyroid and reproductive axes and thermogenesis. This precludes the decrease in energy expenditure of food-deprived mice, enhancing weight loss.33,41,42 Central GH action also regulates glucose homeostasis. GHR inactivation in the ventromedial nucleus of the hypothalamus impairs the capacity to recover from hypoglycemia.43 Moreover, central GHR signaling modulates insulin sensitivity in pregnant mice.36

GHR signaling in the CNS affects not only metabolism, but also several cognitive and neuropsychiatric aspects. The GH/IGF-1 axis and the STAT5 signaling pathway regulate learning, memory, and hippocampal function.44-46 Children and adults with GH deficiency exhibit an increased prevalence of neuropsychiatric diseases, such as anxiety and depression.47 Dos Santos et al.48 demonstrated that GHR ablation in somatostatin-expressing cells increases anxiety-like behavior in mice. These effects are associated with changes in the expression of genes involved in synaptic plasticity and function in the central and basolateral amygdala complex. Somatostatin-specific GHR knockout mice also exhibited reduced fear memory during auditory Pavlovian fear conditioning.48 These findings are in accordance with previous studies showing that GH overexpression in the amygdala increases fear memory and enhances local neuronal activity and dendritic spine density.22,49 Thus, central GHR signaling modulates several neurological aspects, possibly affecting predisposition to neuropsychiatric diseases including anxiety and post-traumatic stress disorder.

ASSOCIATION AMONG GH, INFLAMMATION, AND LONGEVITY

Go to

A remarkable feature of whole-body GHR knockout mice is their increased longevity, reaching nearly 5 years.50,51 GHR knockout or GH-deficient mice are protected against aging-induced decline in insulin sensitivity, memory, and neurological functions.45,52-54 In this section, we discuss the role of GH in regulating inflammation, insulin sensitivity, and longevity either directly via GHR signaling or indirectly by modulating IGF-1 secretion.

GHR signaling has a pro-inflammatory effect on the brain and other tissues

Treatment of Wistar rats with GH for 1 week increases the hypothalamic and hippocampal expression of glial fibrillary acidic protein (GFAP),55 an astroglial marker frequently associated with neuroinflammation and brain damage.56,57 GH oversecretion triggers inflammation in the body58 and some brain regions.59 The GFAP expression in the brain of 3.5-month-old mice oversecreting GH is equivalent to that found in 12-month-old wild-type mice, indicating accelerated aging when the GH/IGF-1 axis is chronically overstimulated.59 In contrast, GHR-deficient mice are protected against age-related NLR family pyrin domain containing 3 inflammasome activation and immune senescence,60 and they present an increased neuron/glia ratio in the cerebral cortex.61 Eighteen-month-old GH-deficient mice exhibit reduced expression of neuroinflammation markers in the hypothalamus compared to control animals.62 GH or GHR deficiency also protects mice against obesity-induced inflammation in the hypothalamus and adipose tissue.63,64 Thus, suppressed activity of the GH axis appears to reduce systemic and brain inflammation. However, since GH or GHR deficiency leads to suppressed IGF-1 expression and secretion, it was unclear until recently whether the lower activity of GH or IGF-1 receptor signaling underlaid these effects.

A recent study confirmed the critical role of the GH/IGF-1 axis in regulating neuroinflammation, initially using mice presenting GH deficiency or oversecretion.30 While GH-deficient mice exhibit reduced hypothalamic expression of GFAP, F4/80, ionized calcium-binding adapter molecule 1 (Iba1), and TNF-α, indicating reduced neuroinflammation, transgenic mice overexpressing GH show the opposite phenotype.30 However, GH and IGF-1 levels are suppressed in GH-deficient mice, whereas these hormones are elevated in the blood of mice oversecreting GH.30 Tissue-specific GHR knockout mice were used to uncover the individual roles of GH and IGF-1 in inducing hypothalamic neuroinflammation. GHR ablation in hepatocytes generates mice with very low circulating IGF-1 level but increased GH secretion, probably due to the loss of IGF-1 negative feedback.30,65 In such cases, hepatocyte-specific GHR knockout mice show increased hypothalamic expression of GFAP, Iba1, and TNF-α, suggesting increased neuroinflammation in the hypothalamus.30 In contrast, GHR ablation in nestin-expressing cells, which comprise neurons and part of glial cells, decreases the expression of GFAP and F4/80 in the hypothalamus, indicating reduced neuroinflammation.30 These results suggest that the protection against neuroinflammation observed in GH- or GHR-deficient mice is not explained by reduced IGF-1 secretion but rather by decreased GHR signaling in the brain. Thus, GHR signaling has a direct pro-inflammatory effect on the hypothalamus, independent of changes in IGF-1 secretion (Fig. 2).

Several pieces of evidence indicate that the pro-inflammatory effect of GHR signaling involves activation of nuclear factor kappa B (NF-kB). GH-releasing hormone (GHRH)-deficient mice or administration of GHRH antagonists in wild-type mice, conditions that suppress GH secretion, decrease the expression of NF-kB in the prefrontal cortex.66 GH activates the NF-kB pathway in growth plate chondrogenesis to promote longitudinal bone growth.67 In vitro GH treatment in macrophages stimulates the production of pro-inflammatory cytokines, such as IL-1β, interferon-γ, IL-12, C-C motif chemokine ligand 5 (CCL5), and CCL3, via NF-kB-dependent mechanisms.68 GH also increases NF-kB activity in preadipocytes, leading to higher inflammatory response and stimulation of multiple pro-inflammatory cytokines, including TNF-α, IL-6, and CCL2.69

GH presents neuroprotective and neuroregenerative effects upon injury

Although chronic inflammation produces negative consequences, acute inflammation is essential during tissue damage and recovery. In this regard, GH and IGF-1 can regulate inflammation and act as growth factors contributing to tissue regeneration.70 GH treatment improves neuron survival, reduces apoptosis, decreases the expression of inflammatory mediators, and enhances the expression of neurotrophic factors in chicken embryos exposed to hypoxia.71,72 GH also presents neuroprotective effects against excitotoxicity and increases the expression of neurotrophins and growth factors in chicken neuroretinal cells.73 Preliminary evidence suggests that GH treatment has a beneficial effect on spinal cord injury.74 GH administration improves motor function in rats with spinal cord injury.75 Topical application of GH in rats improves neuronal function and attenuates edema formation and cell injury after spinal cord injury.76 A recent study demonstrated that GH treatment enhances the recovery of spinal cord-lesioned animals and presents an anti-inflammatory effect.77 Thus, the pro-inflammatory effect of GHR signaling in normal physiological conditions or chronically elevated GH secretion is not observed during brain injury. Conversely, GH seems to have an anti-inflammatory effect in this situation and contributes to neuroregeneration.

IGF-1 ACTION IN THE BRAIN REGULATES NUMEROUS NEUROLOGICAL FUNCTIONS AND DEVELOPMENT

Go to

Despite the evidence that GHR signaling directly influences inflammation and other physiological aspects of the brain, the IGF-1 receptor is widely expressed in neuronal and glial cells.78 IGF-1 robustly stimulates 2-deoxyglucose uptake in glial cells but not neurons, suggesting signaling via insulin receptors in glial cells.78 IGF-1 can also act as a neurotrophic growth factor in neurons and glial cells.78 Additionally, IGF-1 is critical in brain development, maturation, and neuroplasticity.79-82 IGF-1 stimulates neurogenesis and synaptic plasticity.83-86 For example, IGF-1 treatment increases the expression of N-methyl-D-aspartate receptor subunits in the rat hippocampus.84 IGF-1 can modulate synaptic plasticity in the prefrontal cortex and basolateral amygdala to affect fear memory.85,86 IGF-1 is also involved in wound repair after brain damage.87,88 Thus, IGF-1 is an essential modulator of various neurological functions, including those in development, and can have either GH-independent or -dependent effects on the CNS.

ASSOCIATION AMONG GH, OBESITY, DIABETES MELLITUS, AND LONGEVITY

Go to

As GH prevents high lipolytic activity, GH or GHR deficiency leads to increased body fat percentage. Conversely, patients with acromegaly may exhibit decreased adiposity.89-91 Obese individuals frequently present reduced blood GH levels.92,93 The reasons for this reduction are unknown, but some authors suggest that GH secretion is suppressed by increased fatty acid flux89,93 and insulin levels,92 which are elevated in obese subjects. Thus, GH replacement has been considered a potential therapy for obesity treatment. Although GH treatment slightly reduces body adiposity, some limitations were observed, mainly because GH causes insulin resistance.93,94

Overnutrition increases endoplasmic reticulum stress in the hypothalamus, which activates NF-kB signaling.95 Activation of NF-kB in the hypothalamus decreases insulin sensitivity and favors the development of obesity.95,96 Patients with acromegaly exhibit decreased insulin sensitivity and a higher risk of developing type 2 diabetes mellitus.97,98 Conversely, the reduced activation of pro-inflammatory pathways in GH- or GHR-deficient animals likely contributes to their increased insulin sensitivity. Several studies also suggest that the GH-induced increase in fatty acid flux leads to lipotoxicity in several tissues, explaining the diabetogenic effect of GH.89 Thus, decreased GH secretion in obese individuals has a beneficial effect on glucose homeostasis, although a probable reduction in GH-induced lipolytic effect occurs in obesity.

The increased insulin sensitivity in GH- and GHR-deficient mice likely impacts longevity positively. Accordingly, centenarians present lower insulin resistance and more highly preserved β-cell function than non-centenarians.99 Decreased insulin/IGF-1 signaling increases lifespan more than two-fold in Caenorhabditis elegans.100 Since insulin and IGF-1 share the same intracellular signaling pathway, insulin and IGF-1 resistance can emerge simultaneously.101 Notably, Alzheimer’s disease patients exhibit insulin and IGF-1 resistance in the brain, which are associated with cognitive decline.101 In addition to insulin resistance, neuroinflammation is also associated with neurodegenerative and neuropsychiatric diseases.102,103 For example, neuroinflammation is a hallmark of Alzheimer’s and Parkinson’s diseases.104,105 Additionally, clinical and preclinical evidence indicates that neuroinflammation plays a significant role in the neurobiological dysfunctions associated with major depressive disorder.103 Since GHR signaling in different areas of the brain stimulates the NF-kB pathway, pro-inflammatory cytokine production, and insulin/IGF-1 resistance, these effects influence the predisposition to metabolic and neurological diseases and impact longevity.106,107

CONCLUSION

Go to

This review presents the current evidence for association among GH action in the brain and other tissues, inflammation, and longevity. As GH secretion declines during aging,26,108 it is tempting to speculate that reduced GH secretion during aging may protect against its negative effects since GHR signaling stimulates neuroinflammation and insulin resistance (Fig. 3). Although it was not in the scope of the present review to discuss the role of GH in stimulating cell proliferation, it is possible that aging-induced suppression of GH secretion may have a beneficial effect in preventing cancer.109 The remarkable increase in longevity in GH- and GHR-deficient animals and their observed protection against several age-related problems, including metabolic, neurodegenerative, and cancer diseases, have sparked discussions about the benefits of GH deficiency (either genetically or physiologically induced).109 On the other hand, considerable evidence demonstrates the physiological importance of GHR signaling in neuroprotective and neuroregenerative effects upon injury,70-77 as well as its critical role in homeostasis under metabolic stress108 and several other positive effects (Fig. 3). Therefore, like numerous other physiological systems, ideal activity of the GH/IGF-1 axis is likely required to promote health, and both excess and absence of GH action can cause undesired consequences that impact the quality of life, the predisposition to diseases, and longevity (Fig. 3).

ACKNOWLEDGMENTS

Go to

The authors are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP/Brazil; grant numbers 2013/07607-8 to Licio A. Velloso and 2020/01318-8 to Jose Donato Jr.) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil; grant number: 306024/2023-3 to Jose Donato Jr.).

Figures

Go to
Fig. 1. Environmental and biological factors that cause chronic lowgrade inflammation and increase the risk of several chronic, non-communicable diseases. Created with BioRender.com.
Fig. 2. Evidence indicates that growth hormone (GH) induces insulin resistance and directly increases inflammation in the hypothalamus, independent of insulin-like growth factor 1 (IGF-1) secretion. Increased inflammation and insulin resistance favor the development of metabolic imbalances (e.g., obesity and diabetes), neurodegeneration (e.g., Alzheimer’s disease), and accelerate aging. Created with BioRender.com.
Fig. 3. Summary of the major positive and negative biological effects of growth hormone (GH) on aging. Both excess and absence of GH action can cause undesired consequences that impact the quality of life, the predisposition to diseases, and longevity. Created with Bio- Render.com. IGF-1, insulin-like growth factor 1.

References

Go to
  1. Kotas ME, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell 2015;160:816-27.
    Pubmed KoreaMed CrossRef
  2. Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature 2017;542:177-85.
    Pubmed CrossRef
  3. Sundaram B, Tweedell RE, Prasanth Kumar S, Kanneganti TD. The NLR family of innate immune and cell death sensors. Immunity 2024;57:674-99.
    Pubmed CrossRef
  4. de Baat A, Trinh B, Ellingsgaard H, Donath MY. Physiological role of cytokines in the regulation of mammalian metabolism. Trends Immunol 2023;44:613-27.
    Pubmed CrossRef
  5. Velloso LA, Folli F, Saad MJ. TLR4 at the crossroads of nutrients, gut microbiota, and metabolic inflammation. Endocr Rev 2015;36:245-71.
    Pubmed CrossRef
  6. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87-91.
    Pubmed CrossRef
  7. Coope A, Torsoni AS, Velloso LA. Mechanisms in endocrinology: metabolic and inflammatory pathways on the pathogenesis of type 2 diabetes. Eur J Endocrinol 2016;174:R175-87.
    Pubmed CrossRef
  8. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 2009;29:359-70.
    Pubmed KoreaMed CrossRef
  9. Engel DF, Velloso LA. The timeline of neuronal and glial alterations in experimental obesity. Neuropharmacology 2022;208:108983.
    Pubmed CrossRef
  10. Shortt C, Hasselwander O, Meynier A, Nauta A, Fernández EN, Putz P, et al. Systematic review of the effects of the intestinal microbiota on selected nutrients and non-nutrients. Eur J Nutr 2018;57:25-49.
    Pubmed KoreaMed CrossRef
  11. de Vos WM, Tilg H, Van Hul M, Cani PD. Gut microbiome and health: mechanistic insights. Gut 2022;71:1020-32.
    Pubmed KoreaMed CrossRef
  12. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003;112:1821-30.
    Pubmed KoreaMed CrossRef
  13. Razolli DS, Moraes JC, Morari J, Moura RF, Vinolo MA, Velloso LA. TLR4 expression in bone marrow-derived cells is both necessary and sufficient to produce the insulin resistance phenotype in diet-induced obesity. Endocrinology 2015;156:103-13.
    Pubmed CrossRef
  14. Prada PO, Zecchin HG, Gasparetti AL, Torsoni MA, Ueno M, Hirata AE, et al. Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion. Endocrinology 2005;146:1576-87.
    Pubmed CrossRef
  15. Shaikh SR, Beck MA, Alwarawrah Y, MacIver NJ. Emerging mechanisms of obesity-associated immune dysfunction. Nat Rev Endocrinol 2024;20:136-48.
    Pubmed CrossRef
  16. Sawada K, Chung H, Softic S, Moreno-Fernandez ME, Divanovic S. The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease. Cell Metab 2023;35:1852-71.
    Pubmed KoreaMed CrossRef
  17. Hosoki S, Hansra GK, Jayasena T, Poljak A, Mather KA, Catts VS, et al. Molecular biomarkers for vascular cognitive impairment and dementia. Nat Rev Neurol 2023;19:737-53.
    Pubmed CrossRef
  18. Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol 2009;6:399-409.
    Pubmed CrossRef
  19. Furigo IC, Metzger M, Teixeira PD, Soares CR, Donato J Jr. Distribution of growth hormone-responsive cells in the mouse brain. Brain Struct Funct 2017;222:341-63.
    Pubmed CrossRef
  20. Kastrup Y, Le Grevès M, Nyberg F, Blomqvist A. Distribution of growth hormone receptor mRNA in the brain stem and spinal cord of the rat. Neuroscience 2005;130:419-25.
    Pubmed CrossRef
  21. de Lima JB, Debarba LK, Rupp AC, Qi N, Ubah C, Khan M, et al. ARCGHR neurons regulate muscle glucose uptake. Cells 2021;10:1093.
    Pubmed KoreaMed CrossRef
  22. Meyer RM, Burgos-Robles A, Liu E, Correia SS, Goosens KA. A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear. Mol Psychiatry 2014;19:1284-94.
    Pubmed KoreaMed CrossRef
  23. Sun LY, Al-Regaiey K, Masternak MM, Wang J, Bartke A. Local expression of GH and IGF-1 in the hippocampus of GH-deficient long-lived mice. Neurobiol Aging 2005;26:929-37.
    Pubmed CrossRef
  24. Pan W, Yu Y, Cain CM, Nyberg F, Couraud PO, Kastin AJ. Permeation of growth hormone across the blood-brain barrier. Endocrinology 2005;146:4898-904.
    Pubmed CrossRef
  25. Menezes F, Wasinski F, de Souza GO, Nunes AP, Bernardes ES, Dos Santos SN, et al. The pattern of GH action in the mouse brain. Endocrinology 2024;165:bqae057.
    Pubmed CrossRef
  26. Dehkhoda F, Lee CM, Medina J, Brooks AJ. The growth hormone receptor: mechanism of receptor activation, cell signaling, and physiological aspects. Front Endocrinol (Lausanne) 2018;9:35.
    Pubmed KoreaMed CrossRef
  27. Wasinski F, Klein MO, Bittencourt JC, Metzger M, Donato J Jr. Distribution of growth hormone-responsive cells in the brain of rats and mice. Brain Res 2021;1751:147189.
    Pubmed CrossRef
  28. Cady G, Landeryou T, Garratt M, Kopchick JJ, Qi N, Garcia-Galiano D, et al. Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons. Mol Metab 2017;6:393-405.
    Pubmed KoreaMed CrossRef
  29. Donato J Jr, Kopchick JJ. New findings on brain actions of growth hormone and potential clinical implications. Rev Endocr Metab Disord 2024;25:541-53.
    Pubmed KoreaMed CrossRef
  30. Wasinski F, Tavares MR, Gusmao DO, List EO, Kopchick JJ, Alves GA, et al. Central growth hormone action regulates neuroglial and proinflammatory markers in the hypothalamus of male mice. Neurosci Lett 2023;806:137236.
    Pubmed KoreaMed CrossRef
  31. List EO, Berryman DE, Funk K, Jara A, Kelder B, Wang F, et al. Liver-specific GH receptor gene-disrupted (LiGHRKO) mice have decreased endocrine IGF-I, increased local IGF-I, and altered body size, body composition, and adipokine profiles. Endocrinology 2014;155:1793-805.
    Pubmed KoreaMed CrossRef
  32. Donato J Jr, Wasinski F, Furigo IC, Metzger M, Frazão R. Central regulation of metabolism by growth hormone. Cells 2021;10:129.
    Pubmed KoreaMed CrossRef
  33. Furigo IC, Teixeira PD, de Souza GO, Couto GC, Romero GG, Perelló M, et al. Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. Nat Commun 2019;10:662.
    Pubmed KoreaMed CrossRef
  34. Zhong C, Song Y, Wang Y, Zhang T, Duan M, Li Y, et al. Increased food intake in growth hormone-transgenic common carp (Cyprinus carpio L.) may be mediated by upregulating Agouti-related protein (AgRP). Gen Comp Endocrinol 2013;192:81-8.
    Pubmed CrossRef
  35. Bohlooly-Y M, Olsson B, Bruder CE, Lindén D, Sjögren K, Bjursell M, et al. Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia. Diabetes 2005;54:51-62.
    Pubmed CrossRef
  36. Teixeira PD, Couto GC, Furigo IC, List EO, Kopchick JJ, Donato J Jr. Central growth hormone action regulates metabolism during pregnancy. Am J Physiol Endocrinol Metab 2019;317:E925-40.
    Pubmed KoreaMed CrossRef
  37. Quaresma PG, Teixeira PD, Furigo IC, Wasinski F, Couto GC, Frazão R, et al. Growth hormone/STAT5 signaling in proopiomelanocortin neurons regulates glucoprivic hyperphagia. Mol Cell Endocrinol 2019;498:110574.
    Pubmed KoreaMed CrossRef
  38. Dos Santos WO, Wasinski F, Tavares MR, Campos AM, Elias CF, List EO, et al. Ablation of growth hormone receptor in GABAergic neurons leads to increased pulsatile growth hormone secretion. Endocrinology 2022;163:bqac103.
    Pubmed KoreaMed CrossRef
  39. Wasinski F, Barrile F, Pedroso JA, Quaresma PG, Dos Santos WO, List EO, et al. Ghrelin-induced food intake, but not GH secretion, requires the expression of the GH receptor in the brain of male mice. Endocrinology 2021;162:bqab097.
    Pubmed KoreaMed CrossRef
  40. Gupta D, Patterson AM, Osborne-Lawrence S, Bookout AL, Varshney S, Shankar K, et al. Disrupting the ghrelin-growth hormone axis limits ghrelin's orexigenic but not glucoregulatory actions. Mol Metab 2021;53:101258.
    Pubmed KoreaMed CrossRef
  41. de Lima JB, Ubah C, Debarba LK, Ayyar I, Didyuk O, Sadagurski M. Hypothalamic GHR-SIRT1 axis in fasting. Cells 2021;10:891.
    Pubmed KoreaMed CrossRef
  42. Stilgenbauer L, de Lima JB, Debarba LK, Khan M, Koshko L, Kopchick JJ, et al. Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in a sex-specific manner. Geroscience 2023;45:1745-59.
    Pubmed KoreaMed CrossRef
  43. Furigo IC, de Souza GO, Teixeira PD, Guadagnini D, Frazão R, List EO, et al. Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons. FASEB J 2019;33:11909-24.
    Pubmed KoreaMed CrossRef
  44. Furigo IC, Melo HM, Lyra E Silva NM, Ramos-Lobo AM, Teixeira PD, Buonfiglio DC, et al. Brain STAT5 signaling modulates learning and memory formation. Brain Struct Funct 2018;223:2229-41.
    Pubmed CrossRef
  45. Basu A, McFarlane HG, Kopchick JJ. Spatial learning and memory in male mice with altered growth hormone action. Horm Behav 2017;93:18-30.
    Pubmed CrossRef
  46. Molina DP, Ariwodola OJ, Weiner JL, Brunso-Bechtold JK, Adams MM. Growth hormone and insulin-like growth factor-I alter hippocampal excitatory synaptic transmission in young and old rats. Age (Dordr) 2013;35:1575-87.
    Pubmed KoreaMed CrossRef
  47. Karachaliou FH, Karavanaki K, Simatou A, Tsintzou E, Skarakis NS, Kanaka-Gatenbein C. Association of growth hormone deficiency (GHD) with anxiety and depression: experimental data and evidence from GHD children and adolescents. Hormones (Athens) 2021;20:679-89.
    Pubmed CrossRef
  48. Dos Santos WO, Juliano VA, Chaves FM, Vieira HR, Frazao R, List EO, et al. Growth hormone action in somatostatin neurons regulates anxiety and fear memory. J Neurosci 2023;43:6816-29.
    Pubmed KoreaMed CrossRef
  49. Gisabella B, Farah S, Peng X, Burgos-Robles A, Lim SH, Goosens KA. Growth hormone biases amygdala network activation after fear learning. Transl Psychiatry 2016;6:e960.
    Pubmed KoreaMed CrossRef
  50. Bartke A, List EO, Kopchick JJ. The somatotropic axis and aging: benefits of endocrine defects. Growth Horm IGF Res 2016;27:41-5.
    Pubmed KoreaMed CrossRef
  51. Junnila RK, Duran-Ortiz S, Suer O, Sustarsic EG, Berryman DE, List EO, et al. Disruption of the GH receptor gene in adult mice increases maximal lifespan in females. Endocrinology 2016;157:4502-13.
    Pubmed CrossRef
  52. Hascup KN, Lynn MK, Fitzgerald PJ, Randall S, Kopchick JJ, Boger HA, et al. Enhanced cognition and hypoglutamatergic signaling in a growth hormone receptor knockout mouse model of successful aging. J Gerontol A Biol Sci Med Sci 2017;72:329-37.
    Pubmed KoreaMed CrossRef
  53. Li X, McPherson M, Hager M, Fang Y, Bartke A, Miller RA. Transient early life growth hormone exposure permanently alters brain, muscle, liver, macrophage, and adipocyte status in long-lived Ames dwarf mice. FASEB J 2022;36:e22394.
    Pubmed KoreaMed CrossRef
  54. Kinney BA, Coschigano KT, Kopchick JJ, Steger RW, Bartke A. Evidence that age-induced decline in memory retention is delayed in growth hormone resistant GH-R-KO (Laron) mice. Physiol Behav 2001;72:653-60.
    Pubmed CrossRef
  55. Baquedano E, Chowen JA, Argente J, Frago LM. Differential effects of GH and GH-releasing peptide-6 on astrocytes. J Endocrinol 2013;218:263-74.
    Pubmed CrossRef
  56. Norden DM, Trojanowski PJ, Villanueva E, Navarro E, Godbout JP. Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia 2016;64:300-16.
    Pubmed KoreaMed CrossRef
  57. Lan X, Han X, Li Q, Yang QW, Wang J. Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat Rev Neurol 2017;13:420-33.
    Pubmed KoreaMed CrossRef
  58. Poudel SB, Ruff RR, Yildirim G, Dixit M, Michot B, Gibbs JL, et al. Excess growth hormone triggers inflammation-associated arthropathy, subchondral bone loss, and arthralgia. Am J Pathol 2023;193:829-42.
    Pubmed KoreaMed CrossRef
  59. Miller DB, Bartke A, O'Callaghan JP. Increased glial fibrillary acidic protein (GFAP) levels in the brains of transgenic mice expressing the bovine growth hormone (bGH) gene. Exp Gerontol 1995;30:383-400.
    Pubmed CrossRef
  60. Spadaro O, Goldberg EL, Camell CD, Youm YH, Kopchick JJ, Nguyen KY, et al. Growth hormone receptor deficiency protects against age-related NLRP3 inflammasome activation and immune senescence. Cell Rep 2016;14:1571-80.
    Pubmed KoreaMed CrossRef
  61. Ransome MI, Goldshmit Y, Bartlett PF, Waters MJ, Turnley AM. Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness. Eur J Neurosci 2004;19:2069-79.
    Pubmed CrossRef
  62. Sadagurski M, Landeryou T, Cady G, Kopchick JJ, List EO, Berryman DE, et al. Growth hormone modulates hypothalamic inflammation in long-lived pituitary dwarf mice. Aging Cell 2015;14:1045-54.
    Pubmed KoreaMed CrossRef
  63. Baquedano E, Ruiz-Lopez AM, Sustarsic EG, Herpy J, List EO, Chowen JA, et al. The absence of GH signaling affects the susceptibility to high-fat diet-induced hypothalamic inflammation in male mice. Endocrinology 2014;155:4856-67.
    Pubmed CrossRef
  64. Young JA, Henry BE, Benencia F, Bell S, List EO, Kopchick JJ, et al. GHR-/- mice are protected from obesity-related white adipose tissue inflammation. J Neuroendocrinol 2020;32:e12854.
    Pubmed KoreaMed CrossRef
  65. Gusmao DO, de Sousa ME, Tavares MR, Donato J. Increased GH secretion and body growth in mice carrying ablation of IGF-1 receptor in GH-releasing hormone cells. Endocrinology 2022;163:bqac151.
    Pubmed CrossRef
  66. Recinella L, Libero ML, Veschi S, Piro A, Marconi GD, Diomede F, et al. Effects of GHRH deficiency and GHRH antagonism on emotional disorders in mice. Cells 2023;12:2615.
    Pubmed KoreaMed CrossRef
  67. De Luca F. Regulatory role of NF-κB in growth plate chondrogenesis and its functional interaction with growth hormone. Mol Cell Endocrinol 2020;514:110916.
    Pubmed CrossRef
  68. Sodhi A, Tripathi A. Prolactin and growth hormone induce differential cytokine and chemokine profile in murine peritoneal macrophages in vitro: involvement of p-38 MAP kinase, STAT3 and NF-kappaB. Cytokine 2008;41:162-73.
    Pubmed CrossRef
  69. Kumar PA, Chitra PS, Lu C, Sobhanaditya J, Menon R. Growth hormone (GH) differentially regulates NF-kB activity in preadipocytes and macrophages: implications for GH's role in adipose tissue homeostasis in obesity. J Physiol Biochem 2014;70:433-40.
    Pubmed CrossRef
  70. Bianchi VE, Locatelli V, Rizzi L. Neurotrophic and neuroregenerative effects of GH/IGF1. Int J Mol Sci 2017;18:2441.
    Pubmed KoreaMed CrossRef
  71. Baltazar-Lara R, Zenil JM, Carranza M, Ávila-Mendoza J, Martínez-Moreno CG, Arámburo C, et al. Growth hormone (GH) crosses the blood-brain barrier (BBB) and induces neuroprotective effects in the embryonic chicken cerebellum after a hypoxic injury. Int J Mol Sci 2022;23:11546.
    Pubmed KoreaMed CrossRef
  72. Olivares-Hernández JD, Carranza M, Balderas-Márquez JE, Epardo D, Baltazar-Lara R, Ávila-Mendoza J, et al. Neuroprotective and regenerative effects of growth hormone (GH) in the embryonic chicken cerebral pallium exposed to hypoxic-ischemic (HI) injury. Int J Mol Sci 2022;23:9054.
    Pubmed KoreaMed CrossRef
  73. Martinez-Moreno CG, Fleming T, Carranza M, Ávila-Mendoza J, Luna M, Harvey S, et al. Growth hormone protects against kainate excitotoxicity and induces BDNF and NT3 expression in chicken neuroretinal cells. Exp Eye Res 2018;166:1-12.
    Pubmed CrossRef
  74. Díaz-Galindo MD, Calderón-Vallejo D, Olvera-Sandoval C, Quintanar JL. Therapeutic approaches of trophic factors in animal models and in patients with spinal cord injury. Growth Factors 2020;38:1-15.
    Pubmed CrossRef
  75. Hanci M, Kuday C, Oğuzoğlu SA. The effects of synthetic growth hormone on spinal cord injury. J Neurosurg Sci 1994;38:43-9.
  76. Winkler T, Sharma HS, Stålberg E, Badgaiyan RD, Westman J, Nyberg F. Growth hormone attenuates alterations in spinal cord evoked potentials and cell injury following trauma to the rat spinal cord: an experimental study using topical application of rat growth hormone. Amino Acids 2000;19:363-71.
    Pubmed CrossRef
  77. Martínez-Moreno CG, Calderón-Vallejo D, Díaz-Galindo C, Hernández-Jasso I, Olivares-Hernández JD, Ávila-Mendoza J, et al. Gonadotropin-releasing hormone and growth hormone act as anti-inflammatory factors improving sensory recovery in female rats with thoracic spinal cord injury. Front Neurosci 2023;17:1164044.
    Pubmed KoreaMed CrossRef
  78. Shemer J, Raizada MK, Masters BA, Ota A, LeRoith D. Insulin-like growth factor I receptors in neuronal and glial cells. Characterization and biological effects in primary culture. J Biol Chem 1987;262:7693-9.
    Pubmed CrossRef
  79. Dyer AH, Vahdatpour C, Sanfeliu A, Tropea D. The role of insulin-like growth factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience 2016;325:89-99.
    Pubmed CrossRef
  80. Ni W, Rajkumar K, Nagy JI, Murphy LJ. Impaired brain development and reduced astrocyte response to injury in transgenic mice expressing IGF binding protein-1. Brain Res 1997;769:97-107.
    Pubmed CrossRef
  81. Carson MJ, Behringer RR, Brinster RL, McMorris FA. Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 1993;10:729-40.
    Pubmed CrossRef
  82. Ye P, Li L, Richards RG, DiAugustine RP, D'Ercole AJ. Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 2002;22:6041-51.
    Pubmed KoreaMed CrossRef
  83. Åberg D. Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis. Endocr Dev 2010;17:63-76.
    Pubmed CrossRef
  84. Le Grevès M, Le Grevès P, Nyberg F. Age-related effects of IGF-1 on the NMDA-, GH- and IGF-1-receptor mRNA transcripts in the rat hippocampus. Brain Res Bull 2005;65:369-74.
    Pubmed CrossRef
  85. Maglio LE, Noriega-Prieto JA, Maroto IB, Martin-Cortecero J, Muñoz-Callejas A, Callejo-Móstoles M, et al. IGF-1 facilitates extinction of conditioned fear. Elife 2021;10:e67267.
    Pubmed KoreaMed CrossRef
  86. Champarini LG, Herrera ML, Comas Mutis RG, Espejo PJ, Molina VA, Calfa GD, et al. Effect of intra-BLA overexpression of IGF-1 on the expression of a contextual fear memory trace. Hippocampus 2022;32:765-75.
    Pubmed CrossRef
  87. Beilharz EJ, Russo VC, Butler G, Baker NL, Connor B, Sirimanne ES, et al. Co-ordinated and cellular specific induction of the components of the IGF/IGFBP axis in the rat brain following hypoxic-ischemic injury. Brain Res Mol Brain Res 1998;59:119-34.
    Pubmed CrossRef
  88. Saatman KE, Contreras PC, Smith DH, Raghupathi R, McDermott KL, Fernandez SC, et al. Insulin-like growth factor-1 (IGF-1) improves both neurological motor and cognitive outcome following experimental brain injury. Exp Neurol 1997;147:418-27.
    Pubmed CrossRef
  89. Kopchick JJ, Berryman DE, Puri V, Lee KY, Jorgensen JO. The effects of growth hormone on adipose tissue: old observations, new mechanisms. Nat Rev Endocrinol 2020;16:135-46.
    Pubmed KoreaMed CrossRef
  90. Huang J, Siyar S, Sharma R, Herrig I, Wise L, Aidt S, et al. Adipocyte subpopulations mediate growth hormone-induced lipolysis and glucose tolerance in male mice. Endocrinology 2023;164:bqad151.
    Pubmed CrossRef
  91. Guevara-Aguirre J, Teran E, Lescano D, Guevara A, Guevara C, Longo V, et al. Growth hormone receptor deficiency in humans associates to obesity, increased body fat percentage, a healthy brain and a coordinated insulin sensitivity. Growth Horm IGF Res 2020;51:58-64.
    Pubmed CrossRef
  92. Huang Z, Lu X, Huang L, Chen Y, Zhang C, Veldhuis JD, et al. Suppression of hyperinsulinemia restores growth hormone secretion and metabolism in obese mice. J Endocrinol 2021;250:105-16.
    Pubmed CrossRef
  93. Hjelholt A, Høgild M, Bak AM, Arlien-Søborg MC, Bæk A, Jessen N, et al. Growth hormone and obesity. Endocrinol Metab Clin North Am 2020;49:239-50.
    Pubmed CrossRef
  94. Mekala KC, Tritos NA. Effects of recombinant human growth hormone therapy in obesity in adults: a meta analysis. J Clin Endocrinol Metab 2009;94:130-7.
    Pubmed CrossRef
  95. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 2008;135:61-73.
    Pubmed KoreaMed CrossRef
  96. Johnson AM, Olefsky JM. The origins and drivers of insulin resistance. Cell 2013;152:673-84.
    Pubmed CrossRef
  97. Luger A, Prager R, Gaube S, Graf H, Klauser R, Schernthaner G. Decreased peripheral insulin sensitivity in acromegalic patients. Exp Clin Endocrinol 1990;95:339-43.
    Pubmed CrossRef
  98. Bredella MA, Schorr M, Dichtel LE, Gerweck AV, Young BJ, Woodmansee WW, et al. Body composition and ectopic lipid changes with biochemical control of acromegaly. J Clin Endocrinol Metab 2017;102:4218-25.
    Pubmed KoreaMed CrossRef
  99. Paolisso G, Barbieri M, Rizzo MR, Carella C, Rotondi M, Bonafè M, et al. Low insulin resistance and preserved beta-cell function contribute to human longevity but are not associated with TH-INS genes. Exp Gerontol 2001;37:149-56.
    Pubmed CrossRef
  100. van Heemst D. Insulin, IGF-1 and longevity. Aging Dis 2010;1:147-57.
  101. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012;122:1316-38.
    Pubmed KoreaMed CrossRef
  102. De Felice FG. Alzheimer's disease and insulin resistance: translating basic science into clinical applications. J Clin Invest 2013;123:531-9.
    Pubmed KoreaMed CrossRef
  103. Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B, et al. Neuroinflammation and depression: a review. Eur J Neurosci 2021;53:151-71.
    Pubmed CrossRef
  104. Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 2021;17:157-72.
    Pubmed CrossRef
  105. Boyd RJ, Avramopoulos D, Jantzie LL, McCallion AS. Neuroinflammation represents a common theme amongst genetic and environmental risk factors for Alzheimer and Parkinson diseases. J Neuroinflammation 2022;19:223.
    Pubmed KoreaMed CrossRef
  106. Masternak MM, Panici JA, Bonkowski MS, Hughes LF, Bartke A. Insulin sensitivity as a key mediator of growth hormone actions on longevity. J Gerontol A Biol Sci Med Sci 2009;64:516-21.
    Pubmed KoreaMed CrossRef
  107. Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, et al. Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp (Warsz) 2016;64:111-26.
    Pubmed CrossRef
  108. Tavares MR, Frazao R, Donato J. Understanding the role of growth hormone in situations of metabolic stress. J Endocrinol 2022;256:e220159.
    Pubmed CrossRef
  109. Basu R, Qian Y, Kopchick JJ. Mechanisms in endocrinology: lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?. Eur J Endocrinol 2018;178:R155-81.
    Pubmed CrossRef

Share this article on :

Related articles in Jomes

more