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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: As an adipokine in circulation, adiponectin has been extensively studied for its beneficial metabolic effects.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.

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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ApoB immunofluorescence in gonadal WAT with quantitation.(A) Representative co-immunofluorescence of apolipoprotein B (ApoB, red) and endomucin (green) on gonadal WAT. (B and C) Quantitation of ApoB immunofluorescence intensity volume normalized against tissue area in subcutaneous WAT (B) and gonadal WAT (C). n ≥ 3 mice per condition. Data are presented as the mean ± SEM. #p < 0.05, ##p < 0.01 for STZ-treated vs untreated Adn+/+. Related to Figure 3F.DOI:http://dx.doi.org/10.7554/eLife.03851.019
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fig3s4: ApoB immunofluorescence in gonadal WAT with quantitation.(A) Representative co-immunofluorescence of apolipoprotein B (ApoB, red) and endomucin (green) on gonadal WAT. (B and C) Quantitation of ApoB immunofluorescence intensity volume normalized against tissue area in subcutaneous WAT (B) and gonadal WAT (C). n ≥ 3 mice per condition. Data are presented as the mean ± SEM. #p < 0.05, ##p < 0.01 for STZ-treated vs untreated Adn+/+. Related to Figure 3F.DOI:http://dx.doi.org/10.7554/eLife.03851.019

Mentions: To determine whether the defective lipid uptake leads to lipoprotein accumulation in subcutaneous WAT, we examined apolipoproteins A1, B, and E (ApoA1, ApoB, and ApoE, major components of high-, low-, and intermediate-density lipoproteins, respectively) in situ by immunofluorescence (Figure 3E–G). Compared to the euglycemic wild-type controls, STZ-treated animals showed elevated signals for apolipoproteins. Interestingly, most of the ApoA1 and ApoE signals, as well as part of the ApoB signal, located adjacent to endomucin, a marker for venous and capillary endothelial cells, reflecting apolipoproteins in circulation. The endomucin signal itself demonstrated increased vascular density in subcutaneous WAT of STZ-treated lipoatrophic animals, which was also observed in gonadal WAT (Figure 3—figure supplement 3–5). Furthermore, adiponectin knockout-induced ApoA1 accumulation was significant in subcutaneous WAT and BAT, but not in gonadal WAT (Figure 3E and Figure 3—figure supplement 3). Compared to STZ-treated wild-type mice, adiponectin mice showed trends towards an increase in ApoB signal in both subcutaneous and gonadal WATs (Figure 3F and Figure 3—figure supplement 4). As for the ApoE signal, there was a trend towards an increase in subcutaneous WAT, but not in gonadal WAT (Figure 3G and Figure 3—figure supplement 5). Collectively, these data suggest an overall accumulation of apolipoproteins in the local circulation of adipose tissues of STZ-treated mice, which is exacerbated by adiponectin depletion predominantly in subcutaneous WAT.


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)

ApoB immunofluorescence in gonadal WAT with quantitation.(A) Representative co-immunofluorescence of apolipoprotein B (ApoB, red) and endomucin (green) on gonadal WAT. (B and C) Quantitation of ApoB immunofluorescence intensity volume normalized against tissue area in subcutaneous WAT (B) and gonadal WAT (C). n ≥ 3 mice per condition. Data are presented as the mean ± SEM. #p < 0.05, ##p < 0.01 for STZ-treated vs untreated Adn+/+. Related to Figure 3F.DOI:http://dx.doi.org/10.7554/eLife.03851.019
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3s4: ApoB immunofluorescence in gonadal WAT with quantitation.(A) Representative co-immunofluorescence of apolipoprotein B (ApoB, red) and endomucin (green) on gonadal WAT. (B and C) Quantitation of ApoB immunofluorescence intensity volume normalized against tissue area in subcutaneous WAT (B) and gonadal WAT (C). n ≥ 3 mice per condition. Data are presented as the mean ± SEM. #p < 0.05, ##p < 0.01 for STZ-treated vs untreated Adn+/+. Related to Figure 3F.DOI:http://dx.doi.org/10.7554/eLife.03851.019
Mentions: To determine whether the defective lipid uptake leads to lipoprotein accumulation in subcutaneous WAT, we examined apolipoproteins A1, B, and E (ApoA1, ApoB, and ApoE, major components of high-, low-, and intermediate-density lipoproteins, respectively) in situ by immunofluorescence (Figure 3E–G). Compared to the euglycemic wild-type controls, STZ-treated animals showed elevated signals for apolipoproteins. Interestingly, most of the ApoA1 and ApoE signals, as well as part of the ApoB signal, located adjacent to endomucin, a marker for venous and capillary endothelial cells, reflecting apolipoproteins in circulation. The endomucin signal itself demonstrated increased vascular density in subcutaneous WAT of STZ-treated lipoatrophic animals, which was also observed in gonadal WAT (Figure 3—figure supplement 3–5). Furthermore, adiponectin knockout-induced ApoA1 accumulation was significant in subcutaneous WAT and BAT, but not in gonadal WAT (Figure 3E and Figure 3—figure supplement 3). Compared to STZ-treated wild-type mice, adiponectin mice showed trends towards an increase in ApoB signal in both subcutaneous and gonadal WATs (Figure 3F and Figure 3—figure supplement 4). As for the ApoE signal, there was a trend towards an increase in subcutaneous WAT, but not in gonadal WAT (Figure 3G and Figure 3—figure supplement 5). Collectively, these data suggest an overall accumulation of apolipoproteins in the local circulation of adipose tissues of STZ-treated mice, which is exacerbated by adiponectin depletion predominantly in subcutaneous WAT.

Bottom Line: As an adipokine in circulation, adiponectin has been extensively studied for its beneficial metabolic effects.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.

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