Central Insulin Signaling Is Attenuated by Long-Term Insulin Exposure via Insulin Receptor Substrate-1 Serine Phosphorylation, Proteasomal Degradation, and Lysosomal Insulin Receptor Degradation

Mayer, Christopher; Belsham, Denise D.

doi:10.1210/en.2009-0838

Cited by 69 publications

(70 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…How cellular insulin resistance can hinder hormonal modulation of POMC neurons in particular is a pressing question that remains to be answered. Similar to previous studies from our laboratory on other hypothalamic cell lines, we found that pretreatment of the mHypoA-POMC/GFP neurons with elevated levels of insulin led to cellular insulin resistance as determined by the inability of insulin to induce Akt phosphorylation (Mayer & Belsham 2010, Nazarians-Armavil et al 2013. However, the changes in gene expression that may accompany hormone resistance in POMC neurons have not yet been addressed and this may be a fundamental aspect of central insulin resistance.…”

Section: Discussionsupporting

confidence: 85%

See 1 more Smart Citation

Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

Nazarians-Armavil¹,

Chalmers²,

Lee³

et al. 2013

Journal of Endocrinology

View full text Add to dashboard Cite

POMC neurons play a central role in the maintenance of whole-body energy homeostasis. This balance requires proper regulation of POMC neurons by metabolic hormones, such as insulin. However, the heterogeneous cellular population of the intact hypothalamus presents challenges for examining the molecular mechanisms underlying the potent anorexigenic effects of POMC neurons, and there is currently a complete lack of mature POMC neuronal cell models for study. To this end, we have generated novel, immortalized, adult-derived POMC-expressing/a-MSH-secreting cell models, mHypoA-POMC/GFP lines 1-4, representing the fluorescence-activated cell-sorted POMC population from primary POMCeGFP mouse hypothalamus. The presence of Pomc mRNA in these cell lines was confirmed, and a-MSH was detected via immunofluorescence. a-MSH secretion in the mHypoA-POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay. Further experiments using the mHypoA-POMC/GFP-1 cell line revealed that 10 ng/ml CNTF increases Pomc mRNA at 1 and 2 h after treatment, whereas insulin elicited an increase in Pomc mRNA level and decreases in insulin receptor (Insr (Ir)) mRNA level at 4 h. Furthermore, the activation of IR-mediated downstream second messengers was examined by western blot analysis, following the induction of cellular insulin resistance, which resulted in a loss of insulin-mediated regulation of Pomc and Ir mRNAs. The development of these immortalized neurons will be invaluable for the elucidation of the cellular and molecular mechanisms that underlie POMC neuronal function under normal and perturbed physiological conditions.

show abstract

Section: Discussionsupporting

confidence: 85%

“…Our laboratory has optimized the procedure for the induction of insulin resistance in neuronal cell lines (Mayer & Belsham 2010, Nazarians-Armavil et al 2013. We have previously established that exposure to a minimum of 100 nM of insulin for 24 h is required to induce a state of insulin resistance in our cell models.…”

Section: Figurementioning

confidence: 99%

Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

Nazarians-Armavil¹,

Chalmers²,

Lee³

et al. 2013

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…The mTOR molecule, a highly conserved nutrient sensor, modulates INS metabolic signaling through its phosphorylation [(P)] of S6K1, an evolutionarily conserved serine (Ser) kinase [16,17,18,19,20,21]. Evidence is mounting that chronic activation of S6K1, by excessive nutrients, promotes INS resistance in fat, liver, heart, skeletal muscle, and renal tissue through increased Ser(P) of the critical INS signaling/docking molecule, INS receptor substrate protein-1 (IRS-1), leading to impaired phosphoinositol 3-kinase (PI3-K) engagement and protein kinase B (Akt) stimulation [21,22,23]. Our recent work indicates that S6K1 is activated in CV tissue of an overnutrition rodent model that exhibits diminished INS metabolic signaling and biological consequences, such as impaired nitric oxide (NO)-mediated vascular relaxation, cardiac diastolic dysfunction, and promotion of kidney tubulointerstitial fibrosis.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Overnutrition on Insulin Metabolic Signaling in the Heart and the Kidney

Pulakat¹,

DeMarco²,

Whaley‐Connell³

et al. 2011

Cardiorenal Med

View full text Add to dashboard Cite

Overnutrition characterized by overconsumption of food rich in fat and carbohydrates is a significant contributor to hypertension, type 2 diabetes, and the cardiorenal syndrome. Overnutrition activates the renin-angiotensin-aldosterone system (RAAS) and causes chronic exposure of cardiovascular and renal tissue to increased circulating nutrients, insulin (INS), and angiotensin II (ANG II). Emerging evidence suggests that overnutrition, aldosterone, and ANG II promote INS resistance, a chronic condition that underlies these co-morbidities, through activation of the mammalian target of the rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling pathway in cardiovascular tissue and the kidney. However, a novel ANG II type 2 receptor (AT₂R)-mediated cross talk between the RAAS and mTOR pathways ameliorates overnutrition-induced activation of mTOR/S6K1 signaling in cardiovascular tissue of rats, mice, and humans and confers cardioprotection.

show abstract

“…Among the substrates, IRS1 is important in activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (4) and its signaling functions are mediated by phosphorylation and acetylation (5,6). Ubiquitination of IRS1 following phosphorylation on Ser307 leads to its proteasome-dependent degradation, which in conjunction with lysosomal degradation of IR, resulting in decrease of insulin sensitivity after long-term stimulation by insulin (7). Insulin-induced IRS1 degradation relies on proteasome-dependent pathway (8), while osmotic stress and oxidative stress enhance IRS1 degradation in a proteasome-independent process (9,10).…”

mentioning

confidence: 99%

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Sun

Tan

Huang

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared to wild type cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of wild type CD36, but not a ubiquitination-defective CD36 mutant delayed Akt activation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multi-subunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.Cell signaling is usually initiated by binding an activating ligand to a receptor on the plasma membrane (PM) that transmits the signal inside the cell. Distinct cellular responses and outcomes of a signaling pathway are achieved by precise regulation of its duration, magnitude and subcellular compartmentalization, which is mediated by an integrated network with multiple http://www.jbc.org/cgi

show abstract

Central Insulin Signaling Is Attenuated by Long-Term Insulin Exposure via Insulin Receptor Substrate-1 Serine Phosphorylation, Proteasomal Degradation, and Lysosomal Insulin Receptor Degradation

Cited by 69 publications

References 46 publications

Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

The Impact of Overnutrition on Insulin Metabolic Signaling in the Heart and the Kidney

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Contact Info

Product

Resources

About