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Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes β-cell regeneration.

Ye R, Holland WL, Gordillo R, Wang M, Wang QA, Shao M, Morley TS, Gupta RK, Stahl A, Scherer PE - Elife (2014)

Bottom Line: When insulin levels are marginal, adiponectin is critical for insulin signaling, endocytosis, and lipid uptake in subcutaneous white adipose tissue.In the absence of both insulin and adiponectin, severe lipoatrophy and hyperlipidemia lead to lethality.In contrast, elevated adiponectin levels improve systemic lipid metabolism in the near absence of insulin.

View Article: PubMed Central - PubMed

Affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.

ABSTRACT
As an adipokine in circulation, adiponectin has been extensively studied for its beneficial metabolic effects. While many important functions have been attributed to adiponectin under high-fat diet conditions, little is known about its essential role under regular chow. Employing a mouse model with inducible, acute β-cell ablation, we uncovered an essential role of adiponectin under insulinopenic conditions to maintain minimal lipid homeostasis. When insulin levels are marginal, adiponectin is critical for insulin signaling, endocytosis, and lipid uptake in subcutaneous white adipose tissue. In the absence of both insulin and adiponectin, severe lipoatrophy and hyperlipidemia lead to lethality. In contrast, elevated adiponectin levels improve systemic lipid metabolism in the near absence of insulin. Moreover, adiponectin is sufficient to mitigate local lipotoxicity in pancreatic islets, and it promotes reconstitution of β-cell mass, eventually reinstating glycemic control. We uncovered an essential new role for adiponectin, with major implications for type 1 diabetes.

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Related in: MedlinePlus

Quantitation of insulin effect on phosphorylation of HSL and Akt.Western blots were quantitated for infrared signal volume subtracting local background. Phosphorylated HSL (A) and Akt (B) were first normalized against the corresponding total protein. The insulin effect on phosphorylation was then calculated by normalizing the insulin-stimulated samples against their corresponding ones before insulin treatment. Data are presented as the mean ± SEM. Related to Figure 4A.DOI:http://dx.doi.org/10.7554/eLife.03851.022
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fig4s1: Quantitation of insulin effect on phosphorylation of HSL and Akt.Western blots were quantitated for infrared signal volume subtracting local background. Phosphorylated HSL (A) and Akt (B) were first normalized against the corresponding total protein. The insulin effect on phosphorylation was then calculated by normalizing the insulin-stimulated samples against their corresponding ones before insulin treatment. Data are presented as the mean ± SEM. Related to Figure 4A.DOI:http://dx.doi.org/10.7554/eLife.03851.022

Mentions: Insulin promotes lipid storage in adipose tissue via stimulating the intracellular insulin signaling cascades leading to enhanced extracellular lipoprotein lipase activity. A low dose of insulin treatment (0.2 mU/g body weight) markedly suppressed the hormone-sensitive lipase (HSL) serine-660 phosphorylation, a marker positively associated with lipolysis, by 57% and induced Akt serine-473 phosphorylation by 8.6-fold in subcutaneous WAT of STZ-treated wild-type mice. However, STZ-treated adiponectin s showed a blunted response in HSL inhibition (41%), and an abolished Akt activation (13%), as compared to the same animal prior to insulin injection (Figure 4A and Figure 4—figure supplement 1). The unchanged post-heparin lipoprotein lipase activity (Figure 4—figure supplement 2) is unlikely to be a major contributing factor to the impaired lipid uptake in the STZ-treated adiponectin animals. The fatty acid translocase CD36 (Figure 4B) and fatty acid transport protein 1 (FATP1) (Figure 4C) are also unlikely contributors, both of which show comparable distributions between genotypes. Expression of Scavenger Receptor Class B Member 1 (SR-B1), a high-density lipoprotein (HDL) receptor, was enhanced in STZ-treated adiponectin knockouts (Figure 4D), which could reflect a compensatory response for the HDL accumulation in circulation (Figure 3E and Figure 3—figure supplement 3C).10.7554/eLife.03851.021Figure 4.Adiponectin is important for caveolar structures and Caveolin-1 expression in subcutaneous white adipose tissue of STZ-treated mice.


Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes β-cell regeneration.

Ye R, Holland WL, Gordillo R, Wang M, Wang QA, Shao M, Morley TS, Gupta RK, Stahl A, Scherer PE - Elife (2014)

Quantitation of insulin effect on phosphorylation of HSL and Akt.Western blots were quantitated for infrared signal volume subtracting local background. Phosphorylated HSL (A) and Akt (B) were first normalized against the corresponding total protein. The insulin effect on phosphorylation was then calculated by normalizing the insulin-stimulated samples against their corresponding ones before insulin treatment. Data are presented as the mean ± SEM. Related to Figure 4A.DOI:http://dx.doi.org/10.7554/eLife.03851.022
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4228265&req=5

fig4s1: Quantitation of insulin effect on phosphorylation of HSL and Akt.Western blots were quantitated for infrared signal volume subtracting local background. Phosphorylated HSL (A) and Akt (B) were first normalized against the corresponding total protein. The insulin effect on phosphorylation was then calculated by normalizing the insulin-stimulated samples against their corresponding ones before insulin treatment. Data are presented as the mean ± SEM. Related to Figure 4A.DOI:http://dx.doi.org/10.7554/eLife.03851.022
Mentions: Insulin promotes lipid storage in adipose tissue via stimulating the intracellular insulin signaling cascades leading to enhanced extracellular lipoprotein lipase activity. A low dose of insulin treatment (0.2 mU/g body weight) markedly suppressed the hormone-sensitive lipase (HSL) serine-660 phosphorylation, a marker positively associated with lipolysis, by 57% and induced Akt serine-473 phosphorylation by 8.6-fold in subcutaneous WAT of STZ-treated wild-type mice. However, STZ-treated adiponectin s showed a blunted response in HSL inhibition (41%), and an abolished Akt activation (13%), as compared to the same animal prior to insulin injection (Figure 4A and Figure 4—figure supplement 1). The unchanged post-heparin lipoprotein lipase activity (Figure 4—figure supplement 2) is unlikely to be a major contributing factor to the impaired lipid uptake in the STZ-treated adiponectin animals. The fatty acid translocase CD36 (Figure 4B) and fatty acid transport protein 1 (FATP1) (Figure 4C) are also unlikely contributors, both of which show comparable distributions between genotypes. Expression of Scavenger Receptor Class B Member 1 (SR-B1), a high-density lipoprotein (HDL) receptor, was enhanced in STZ-treated adiponectin knockouts (Figure 4D), which could reflect a compensatory response for the HDL accumulation in circulation (Figure 3E and Figure 3—figure supplement 3C).10.7554/eLife.03851.021Figure 4.Adiponectin is important for caveolar structures and Caveolin-1 expression in subcutaneous white adipose tissue of STZ-treated mice.

Bottom Line: When insulin levels are marginal, adiponectin is critical for insulin signaling, endocytosis, and lipid uptake in subcutaneous white adipose tissue.In the absence of both insulin and adiponectin, severe lipoatrophy and hyperlipidemia lead to lethality.In contrast, elevated adiponectin levels improve systemic lipid metabolism in the near absence of insulin.

View Article: PubMed Central - PubMed

Affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, United States.

ABSTRACT
As an adipokine in circulation, adiponectin has been extensively studied for its beneficial metabolic effects. While many important functions have been attributed to adiponectin under high-fat diet conditions, little is known about its essential role under regular chow. Employing a mouse model with inducible, acute β-cell ablation, we uncovered an essential role of adiponectin under insulinopenic conditions to maintain minimal lipid homeostasis. When insulin levels are marginal, adiponectin is critical for insulin signaling, endocytosis, and lipid uptake in subcutaneous white adipose tissue. In the absence of both insulin and adiponectin, severe lipoatrophy and hyperlipidemia lead to lethality. In contrast, elevated adiponectin levels improve systemic lipid metabolism in the near absence of insulin. Moreover, adiponectin is sufficient to mitigate local lipotoxicity in pancreatic islets, and it promotes reconstitution of β-cell mass, eventually reinstating glycemic control. We uncovered an essential new role for adiponectin, with major implications for type 1 diabetes.

Show MeSH
Related in: MedlinePlus