Adiponectin Preserves Metabolic Fitness During Aging
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Abstract
Adiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored. Here, we are using an adiponectin null mouse and a transgenic adiponectin overexpression model. We directly assessed the effects of circulating adiponectin on the aging process and found that adiponectin null mice display exacerbated age-related glucose and lipid metabolism disorders. Moreover, adiponectin null mice have a significantly shortened lifespan on both chow and high-fat diet (HFD). In contrast, a transgenic mouse model with elevated circulating adiponectin levels has a dramatically improved systemic insulin sensitivity, reduced age-related tissue inflammation and fibrosis, and a prolonged healthspan and median lifespan. These results support a role of adiponectin as an essential regulator for healthspan and lifespan.
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This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on January 11 2021, follows.
Summary
Adiponectin is a key adipokine, and much of our knowledge about this molecule has come from the Scherer lab. It is well known that adiponectin promotes improved insulin sensitivity and glucose tolerance, along with anti-inflammatory effects, which can be followed by decreased fibrosis. In this paper the Authors use loss and gain of function mouse models to explore whether the beneficial effects of adiponectin on metabolism can be translated into greater healthspan or lifespan. They show that lifespan decreases in adiponectin KOs and increases in the transgenic (ΔGly) mice. The expected effects on glucose metabolism, insulin sensitivity, inflammation, and fibrosis are also demonstrated.
Essential Revisions
This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on January 11 2021, follows.
Summary
Adiponectin is a key adipokine, and much of our knowledge about this molecule has come from the Scherer lab. It is well known that adiponectin promotes improved insulin sensitivity and glucose tolerance, along with anti-inflammatory effects, which can be followed by decreased fibrosis. In this paper the Authors use loss and gain of function mouse models to explore whether the beneficial effects of adiponectin on metabolism can be translated into greater healthspan or lifespan. They show that lifespan decreases in adiponectin KOs and increases in the transgenic (ΔGly) mice. The expected effects on glucose metabolism, insulin sensitivity, inflammation, and fibrosis are also demonstrated.
Essential Revisions
Given the known significant effects of adiponectin on metabolic fitness, the effects on healthspan which the Authors observed in their 2 models, was expected. However, while median survival time is definitely less in the APN-KOs and greater in the ΔGly mice, the effects are relatively modest compared to other longevity studies. Any increase in lifespan is a good thing, particularly when accompanied by a corresponding increase in healthspan. We would've hoped for greater effects on lifespan than those observed but even modest effects are worthwhile. The Authors should comment in their discussion on this point. In other words, it would be good to know the Authors' thinking as to why these impressive effects on glucose, insulin, inflammation, fibrosis, etc. do not lead to even greater effects on lifespan. Also, is there any information on the causes of mortality in the WT vs. KOs that might point to why lifespan is decreased?
APN-KO clearly leads to impaired glucose tolerance, but it is a bit surprising why insulin levels aren't increased, which is the typical metabolic response to insulin resistance.
Can the Authors please comment on adipose tissue mass in the KOs, particularly if they have any information on subq fat?
In Figure 3, they show increased staining for ATMs with Mac2 in the KOs. What about the expression of other inflammatory gene markers, such as those shown in Figure 3G for the liver?
With respect to hepatic effects, this paper shows increased inflammation in the liver in APN-KOs. However these gene expression patterns are in total liver tissue, and it would be helpful to understand the origin of these inflammatory markers. Are they from Kupffer cells, monocyte-derived macrophages, etc. In a similar vein, various fibrosis marker genes are increased in total liver from the APN-KOs. Most likely these expression differences reflect stellate cell effects. Do the Authors have any information on the effect of adiponectin on stellate cell function. Although fibrosis-related genes are elevated in the APN-KO, is there histologic evidence of increased fibrosis in the liver sections?
The Authors suggest that the increased inflammation in the liver is the cause of the increased fibrosis. Presumably they think that the immune cells in the liver are signaling to stellate cells to produce this effect. Is this the scenario the Authors propose. If so, it should be made more explicit and corroborated by histologic staining of hepatic fibrosis.
It would be of interest to know the extent of inflammation in the kidneys with APN-KO, beyond Mac2 staining (Figure 3D).
In the results in the ΔGly mice, is the enhanced lifespan statistically significant. Unless we are misreading it, the p value suggests it is not. Also, why have only study chow fed mice and not HFD mice in the transgenics, as they did in KOs?
ITTs are shown in Figure 4G, but the basal glucose values are different between the 2 groups. Can the Authors also present the data normalized to the basal value to determine whether the kinetics of the curve are different?
The resulting changes in tissue fibrosis are clearly important when thinking about healthy tissue function. It would help if the authors could show histologic staining for collagen deposition in the various tissues, particularly liver and kidney. Although it might be asking for too much if the they don't already have this information, it would also be useful to know which cell types within the various tissues are responsible for the changes in inflammatory markers and collagen related genes. This could also be discussed.
From an aesthetic point of view there is a certain lack symmetry in this paper, since some of the measurements made in the KOs are not performed in the transgenics and HFD was not utilized in the transgenics either.
Much of the data could be predicted from studies by them or the other investigators in the field (Nature Med. 8, 731 (2002), J. Biol. Chem. 277, 25863 (2002), J. Biol. Chem. 277, 34658 (2002), J. Biol. Chem. 278, 2461 (2003), Endocrinology 145, 367 (2004), J. Biol. Chem. 281, 2654 (2006), Am. J. Physiol. Endocrinol. Metab. 293, 210 (2007), J. Clin. Invest. 118, 1645 (2008) . IT would be helpful if authors could provide insights into the life-promoting mechanism by adiponectin that has not been clarified so far.
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