Edition 70 - October 2018 / Subject Review

Subject Review – Ed. 70

Marco A. Rivarola y Alicia Belgorosky. Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina. 

For the Subject Review Section of this issue of Endopedonline, we have selected to comment on a Thematic Review recently published in the Journal of Molecular Endocrinology (T187-T198, 2018) by Rhonda D Kineman et al.:

 

40 YEARS of IGF1

Understanding the tissue-specific roles of IGF1/IGF1R in regulating metabolism using the Cre/loxP system

Rhonda D Kineman1,2 , Mercedes del Rio-Moreno1 and André Sarmento-Cabral1.

1, the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA, and 2, the Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA.

Abstract
It is clear that insulin-like growth factor-1 (IGF1) is important in supporting growth and regulating metabolism. The IGF1 found in the circulation is primarily produced by the liver hepatocytes, but healthy mature hepatocytes do not express appreciable levels of the IGF1 receptor (IGF1R). Therefore, the metabolic actions of IGF1 are thought to be mediated via extra-hepatocyte actions. Given the structural and functional homology between IGF1/IGF1R and insulin receptor (INSR) signaling, and the fact that IGF1, IGF1R and INSR are expressed in most tissues of the body, it is difficult to separate out the tissue-specific contributions of IGF1/IGF1R in maintaining whole body metabolic function. To circumvent this problem, over the last 20 years, investigators have taken advantage of the Cre/loxP system to manipulate IGF1/IGF1R in a tissue-dependent, and more recently, an age-dependent fashion. These studies have revealed that IGF1/IGF1R can alter extra-hepatocyte function to regulate hormonal inputs to the liver and/or alter tissue-specific carbohydrate and lipid metabolism to alter nutrient flux to liver These actions are not mutually exclusive, but serve to integrate the function of all tissues to support the metabolic needs of the organism.

EXCERPTS:

Introduction
In the healthy liver, growth hormone (GH), signaling through the GH receptor (GHR)/JAK2/STAT5B pathway, is required to maintain hepatocyte expression of IGF1, ALS and IGFBP3. Both IGF1 and GH work together to promote longitudinal growth, as well as modulate metabolic function in adults. The metabolic actions of IGF1 are thought to be due to extra-hepatocyte actions. IGF1/IGF1R can alter extra-hepatocyte function to regulate hormonal inputs to the liver and/or alter tissue-specific carbohydrate and lipid metabolism to alter nutrient flux to liver, where these actions are not mutually exclusive, but serve to integrate the function of all tissues to support the metabolic needs of the organism.

“Cre-Lox recombination is a site-specific recombinase technology, used to carry out deletions,  insertionstranslocations and inversions at specific sites in the DNA of cells. It allows the DNA modification to be targeted to a specific cell type or be triggered by a specific external stimulus. It is implemented both in eukaryotic and prokaryotic systems. The Cre-lox recombination system has been particularly useful to help neuroscientists to study the brain in which complex cell types and neural circuits come together to generate cognition and behaviors” (Wikipedia).

 

IGF1 can indirectly regulate (hepatocyte) metabolism through modulation of hormonal inputs.

Hepatocyte-specific reduction in IGF1 increases GH.
In rat models in which circulating IGF1 levels were less than 20% of controls, GH levels were elevated, but structural growth was relatively normal. When circulating IGF1 levels were reduced further, this led to reduced bone growth, but not to the extreme observed in mice with whole-body knockout of IGF1. Therefore, these studies revealed that locally produced IGF1 is critical to support normal growth during development. These studies also indicate that liver-derived, circulating IGF1 mediates some of its metabolic effects indirectly by controlling GH secretion. The metabolic phenotype of mice with hepatocyte IGF1 deficiency is consistent with an increase in GH actions, where GH antagonizes the actions of insulin and enhances lipid oxidation. Also, GH can promote white adipose tissue (WAT) lipolysis under physiologic conditions when relatively unopposed by insulin, or at pathophysiologic levels, as in acromegaly. In the context of normal physiology, these actions of GH are important under fasting conditions, where insulin and IGF1 levels are low and GH levels are elevated, helping to shift nutrient utilization toward lipids, to maintain circulating glucose levels to support neuronal function.

IGF1 works through IGF1R to suppress somatotrope function.
GH is produced by a subpopulation of anterior pituitary cells, called somatotropes. Regulation of somatotrope function is dependent on the hypothalamic neuropeptides, GHRH and somatostatin (SST), which stimulate and inhibit GH secretion, respectively. GH is released into the systemic circulation in a pulsatile fashion, where the pattern of GH release dictates function. GH interacts with multiple target tissues, including the hepatocyte, to stimulate the synthesis of IGF1.
GH and IGF1 feedback at the level of the hypothalamus to reciprocally regulate SST and GHRH input to the pituitary somatotrope, to control GH secretion. Pituitary somatotropes express both IGF1R and INSR, but in vitro IGF1 exclusively works through the IGF1R, not INSR, to suppress somatotrope function.
Both central and pituitary regulatory loops are critical in maintaining appropriate GH output. Insulin promotes WAT glucose uptake, lipid synthesis and storage (anti-lipolytic) and acts directly on hepatocytes to suppress glucose production, stimulate glycogen and lipid production and suppress VLDL triglyceride release. Insulin is also required for maximum hepatocyte expression of IGF1, by augmenting IGF1 gene expression and maintaining hepatocyte GHR expression. Relevant to this review, intact IGF1R signaling is required to maintain normal β-cell function. IGF1R KO mice had reduced expression of Glut2 and glucokinase and a reduction in glucose- and arginine-stimulated insulin release. Taken together, these observations suggest IGF1 works in conjunction with insulin to establish optimal β-cell function to allow appropriate insulin release in response to nutrient stimulation. Also, early loss of one receptor may in part compensate for the loss of the other.

IGF1 works through the IGF1R to enhance pancreatic β-cell function. The metabolic phenotype of mice with hepatocyte IGF1 deficiency is consistent with an increase in GH actions, where GH antagonizes the actions of insulin and enhances lipid oxidation.
Also, GH can promote white adipose tissue (WAT) lipolysis under physiologic conditions. In the context of normal physiology, these actions of GH are important under fasting conditions, where insulin and IGF1 levels are low and GH levels are elevated, helping to shift nutrient utilization toward lipids, to maintain circulating glucose levels to support neuronal function.

IGF1 working through the IGF1R supports thyroid hormone production.
IGF1 working through the IGF1R supports thyroid hormone production. Thyroid hormone, under fasting conditions, reduces insulin sensitivity, promotes lipolysis and directly enhances hepatic glucose output. A direct role in thyroid hormone-mediated hepatic IGF1 production appears to be species specific and concentration dependent. However, IGF1 can directly support thyroid hormone production. This direct action of IGF1 on thyroid function may explain in part the subclinical hypothyroidism observed in patients with isolated GH deficiency. However, the GH-independent actions of IGF1 on thyroid function are somewhat controversial.  

IGF1 working through the IGF1R is essential for granulosa cell (estrogen) development and function. 
Estrogens have profound effects on overall metabolic function, as exemplified by the enhanced prevalence of obesity, insulin resistance, diabetes and fatty liver in post-menopausal compared to normal cycling women.
Recent evidence indicates IGF1 acts directly to modulate granulosa cell development and function. Inhibition of IGF1R signaling in vivo and in vitro using siRNA or pharmacologic strategies, blocks the ability of IGF1 to augment FSH-mediated steroidogenic enzyme production in granulosa cells. In addition, granulosa cell knockout of the IGF1R by crossbreeding Igf1rfl/fl mice with mice heterozygous for both the Esr2-Cre and Cyp19-Cre transgenes, required for maximal recombination, led to the impairment of follicular growth and estrogen production, as well as infertility. Of note, using the same strategy to knockout the INSR in the granulosa cells had no appreciable effect. We might speculate that reduced IGF1 input to granulosa cells during catabolic states may contribute to infertility.
In addition, granulosa cell knockout of the IGF1R by crossbreeding Igf1rfl/fl mice with mice heterozygous for both the Esr2-Cre and Cyp19-Cre transgenes, required for maximal recombination, led to the impairment of follicular growth and estrogen production, as well as infertility.

IGF1R and INSR appear to fully compensate for each other to support normal adrenal and Leydig cell development and function (glucocorticoids/testosterone).
Combined IGF1R/INSR knockout resulted in impaired adrenal cortical and testicular development associated with low glucocorticoid and testosterone production.
Glucocorticoids, derived from the adrenal cortex, stimulate glucose production in the liver, antagonize the actions of insulin and decrease insulin secretion from the pancreatic β-cells. Glucocorticoid receptors (GRs) physically interact with STAT5B in the liver to promote IGF1 and ALS, but at high levels, can decrease the production of IGF1, in part by acting on the hypothalamus to suppress GH secretion.
Androgens have gender-dependent effects on metabolism, many of which are mediated by tissue-specific conversion to estrogen by aromatase. Androgens work in combination with GH/IGF1 to stimulate skeletal and muscle growth
Appropriate models remain to be developed to directly test how IGF1 directly and independently mediates adrenal cortical and Leydig cell function in adults, and how these actions would ultimately influence metabolic function. It should be noted that IGF1 may also support male fertility via regulation of Sertoli cell development; however, Sertoli-specific manipulation of IGF1/IGF1R remains to be explored.  

IGF1 works through the IGF1R to support M2-like macrophage activation
It is now becoming appreciated that the macrophage can transition from a pro-inflammatory (M1) to an anti-inflammatory (M2) state, where differentially expressed cytokines influence adipose and liver metabolism. In general, the M1 phenotype is associated with insulin resistance. Of note, M2 macrophages show high expression of IGF1, relative to M0/M1 macrophages. Knockout of the IGF1R in the myeloid lineage, which includes macrophages, by crossbreeding Igf1rfl/fl mice with LysM-Cre mice reduced expression of M2 markers. When these mice were placed on a high-fat diet, they became more obese and insulin resistant, compared to their IGF1R intact counterparts. These results indicate IGF1 supports an anti-inflammatory macrophage phenotype that may protect against the development of obesity-associated insulin resistance.

IGF1 can indirectly regulate (hepatocyte) metabolism by altering the development and function of key metabolic tissues

IGF1 works through the IGF1R to directly enhance adipose tissue function
Adipose tissue is essential to store nutrients and control glucose/lipid homeostasis, where lack of adipose tissue (lipodystrophy) is associated with extreme systemic insulin resistance and fatty liver. Diet-induced obesity is also associated with adipose tissue insulin resistance and development of fatty liver. Knockout of the INSR in adipocytes had a more severe metabolic phenotype, while combined loss of both IGF1R and INSR resulted in lipodystrophy and ectopic accumulation of fat in the liver and muscle. Although additional follow-up studies are required to understand the full metabolic impact of IGF1 signaling on adipocytes, it is clear the actions of IGF1 are distinct from insulin, where both are required for adipocyte maturation and adult function.

IGF1/IGF1R plays an age-dependent role in muscle development and function
Active muscles preferentially oxidize lipids for energy and promote the overall metabolic health. During myocyte development, IGF1R expression is predominant, while in the differentiated muscle, INSR expression predominates. Crossbreeding Igf1rfl/fl mice with mef-2c-73k promoter-Cre expressed early in development impaired muscle fiber formation and reduced muscle weight, but did not influence glucose homeostasis.
In contrast to the muscle-specific knockout models, muscle IGF1R-lysine-arginine (MKR) mice expressing a dominant-negative mutant IGF1R in skeletal muscle and heart are diabetic with insulin resistance in muscle, liver and adipose tissue. Insulin signaling, not IGF1 signaling, appears to dominate with respect to controlling aspect of mature skeletal and cardiac muscle function.

Summary
Although all the Cre/loxP models have limitations, use of these models has allowed authors to refine their knowledge regarding how IGF1/IGF1R regulates metabolism, independent of the actions of insulin. It is clear from these studies that IGF1/IGF1R acts on many tissues to fine tune metabolism, where future applications of these strategies will continue to focus the understanding of the age-dependent, tissue-specific role IGF1/IGF1R plays in health and disease.

 


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