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Regulation of Insulin sensitivity by Glucocorticoid-Angiopoietin-like 4-Ceramide Axis

Award Number: R01DK113019
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Glucocorticoids (GC) play a key role in metabolic adaptation during stress. However, chronic exposure to GC, is harmful and results in disorders such as insulin resistance. We previously identified angiopoietin-like 4 (Angptl4) as a GC-regulated gene encoding a secreted protein that promotes adipocyte lipolysis and inhibits extracellular lipoprotein lipase (LPL). We showed that Angptl4 is required for GC-promoted lipolysis in white adipose tissue (WAT) and in Angptl4 null mice (Angptl4-/-), excess GC-induced fatty liver and hypertriglyceridemia are diminished. Our recent preliminary studies further demonstrated that GC-induced insulin resistance was compromised in Angptl4-/- mice. Intriguingly, GC treatment increased hepatic ceramide levels, but such GC effect was attenuated in the absence of Angptl4. Indeed, myriocin, which inhibits ceramide synthesis, decreased GC-induced insulin resistance in wild type (WT) but not Angptl4-/- mice. We additionally found that GC exposure elevated the activity of PP2A and PKC¿ (two downstream effectors of ceramides) as well as the expression of a list of ceramide synthetic genes in liver. In Angptl4-/- mice, the activity of PP2A and PKC¿ was mitigated and the expression of ceramide synthase 3-6 (Cers3-6) was specifically impaired. Based on these preliminary data, we hypothesize that GC augment the expression of Angptl4, which promotes WAT lipolysis mobilizing fatty acids (FA) to liver to serve as substrates and signals required for GC to increase Cers3-6 expression. This elevates the production of specific ceramide species to activate PP2A and PKC¿ to suppress insulin action. In this proposal, we will examine this model. In Aim 1, our preliminary study found that the fibrinogen-like domain (FLD) of Angptl4 promotes adipocyte lipolysis without inhibiting LPL. We will test whether FLD restores GC-induced insulin resistance in Angptl4-/- mice. We will also examine the role of FA mobilization to the liver in GC-induced insulin resistance using mice with reduced expression of two major hepatic FA transporters, Fatp5 and Cd36. Moreover, hyperinsulinemic- euglycemic clamps will be used to determine the role of Angptl4 in GC-augmented hepatic glucose production, a hallmark of hepatic insulin resistance. In Aim 2, we will determine which ceramide synthase(s), Cers3-6, are involved in GC-induced insulin resistance. PPARa can be activated by FA and has been shown to increase ceramide synthesis in certain tissues. Thus, its role in GC-induced hepatic Cers3-6 expression and ceramide production will be examined. In Aim 3, we will analyze the role of PP2A and PKC¿ in GC- induced insulin resistance and will identify ceramide synthase(s) that activate PP2A and PKC¿ to cause insulin resistance. Overall, this study will be the first to establish the FLD of Angptl4 as a lipid mobilization factor participating in GC-induced insulin resistance and for the first time, specific ceramide synthases that activate PKC¿ and PP2A will be identified. These findings will advance our understanding of the mechanism of insulin resistance and will provide novel molecular targets for improving insulin sensitivity. ! !


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = -$1 )
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/6/2023	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2021 ( Subtotal = $362,743 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/8/2021	NON-COMPETING CONTINUATION	$36,275
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/13/2020	NON-COMPETING CONTINUATION	$326,468
														Subtotal = $362,743

Issue Date FY: 2020 ( Subtotal = $365,448 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	2/10/2020	NON-COMPETING CONTINUATION	$36,545
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/3/2019	NON-COMPETING CONTINUATION	$328,903
														Subtotal = $365,448

Issue Date FY: 2019 ( Subtotal = $367,907 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/3/2019	NON-COMPETING CONTINUATION	$367,907
														Subtotal = $367,907

Issue Date FY: 2018 ( Subtotal = $370,143 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/7/2017	NEW	$370,143
														Subtotal = $370,143

Grand Total All Awards = $1,466,240

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Regulation of Insulin sensitivity by Glucocorticoid-Angiopoietin-like 4-Ceramide Axis

Award Number: R01DK113019

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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