Adiponectin Reverses β-Cell Damage and Impaired Insulin Secretion Induced by Obesity
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Abstract
Obesity significantly decreases life expectancy and increases the incidence of age-related dysfunctions, including β-cell dysregulation leading to inadequate insulin secretion. Here, we show that diluted plasma from obese human donors acutely impairs β-cell integrity and insulin secretion relative to plasma from lean subjects. Similar results were observed with diluted sera from obese rats fed ad libitum , when compared to sera from lean, calorically-restricted, animals. The damaging effects of obese circulating factors on β-cells occurs in the absence of nutrient overload, and mechanistically involves mitochondrial dysfunction, limiting glucose-supported oxidative phosphorylation and ATP production. We demonstrate that increased levels of adiponectin, as found in lean plasma, are the protective characteristic preserving β-cell function; indeed, sera from adiponectin knockout mice limits β-cell metabolic fluxes relative to controls. Furthermore, oxidative phosphorylation and glucose-sensitive insulin secretion, which are completely abrogated in the absence of this hormone, are restored by the presence of adiponectin alone, surprisingly even in the absence of other serological components, for both the insulin-secreting INS1 cell line and primary islets. The addition of adiponectin to cells treated with plasma from obese donors completely restored β-cell functional integrity, indicating the lack of this hormone was causative of the dysfunction. Overall, our results demonstrate that low circulating adiponectin is a key damaging element for β-cells, and suggest strong therapeutic potential for the modulation of the adiponectin signaling pathway in the prevention of age-related β-cell dysfunction.
Abstract Figure
Graphical Abstract:
Incubation of β-cells with sera or plasma from obese rats and humans hampers mitochondrial oxidative phosphorylation and glucose-stimulated insulin secretion (GSIS) relative to sera and plasma from lean rats and humans. Adiponectin, found at elevated levels in lean subjects, supports β-cell function on its own, in the absence of sera, and also reverses the effects of obese plasma. Prepared using Biorender.com.
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Review coordinated via ASAPbio’s crowd preprint review
This review reflects comments and contributions by Ruchika Bajaj, Pablo Ranea-Robles, Sree Rama Chaitanya Sridhara. Review synthesized by Iratxe Puebla.
In this preprint Munhoz et al. identify adiponectin as the main effector of the protective effects of sera from lean women and calorie-restricted rats on beta-cell integrity and glucose-stimulated insulin secretion. The study reports that sera from obese humans and rats impairs beta-cell integrity and insulin secretion in the absence of nutrient overload. This observation implies that changes in circulating factors between obese and lean individuals would explain the effects on beta-cell function. The levels of circulating adiponectin in rat sera and human plasma were consistent with the metabolic effects observed in beta-cells. …
Review coordinated via ASAPbio’s crowd preprint review
This review reflects comments and contributions by Ruchika Bajaj, Pablo Ranea-Robles, Sree Rama Chaitanya Sridhara. Review synthesized by Iratxe Puebla.
In this preprint Munhoz et al. identify adiponectin as the main effector of the protective effects of sera from lean women and calorie-restricted rats on beta-cell integrity and glucose-stimulated insulin secretion. The study reports that sera from obese humans and rats impairs beta-cell integrity and insulin secretion in the absence of nutrient overload. This observation implies that changes in circulating factors between obese and lean individuals would explain the effects on beta-cell function. The levels of circulating adiponectin in rat sera and human plasma were consistent with the metabolic effects observed in beta-cells. Finally, adding adiponectin to islet cultures that were incubated with sera from obese individuals restored beta-cell integrity and glucose-stimulated insulin secretion. The data are reported in a clear way and the manuscript is well written. Data are consistent with a role of adiponectin in the observed protective effects, but some additional experiments are suggested to clarify this role.
Major comments
- The paper states that adiponectin is necessary to maintain islet function and integrity. According to the data reported, it is recommended to amend the conclusions to indicate that adiponectin is “sufficient”. A key experiment to demonstrate that adiponectin is necessary would be to deplete the sera of adiponectin and then evaluate the same parameters on beta-cells/islet primary culture. Adiponectin-receptor KO beta-cells would also help to clarify the role of adiponectin in the protective effects of sera. It may also be worth exploring if there were other hormones or other components beyond adiponectin which may have the similar increase in serum samples.
- In Figure 3A/3B, a picture of the corresponding Ponceau used for quantification should be shown next to the adiponectin blot. It would also be helpful to provide the full raw blots as supplementary files to allow for further evaluation, e.g. there seems to be a faint band in 3A above the predicted band which might be cropped in 3B, and there seems to be some difference in protein migration in different samples. Please show as a supplementary figure the full blot for adiponectin with all the samples shown in quantification.
- In the blot in Figure 3B there does not appear to be a clear difference between adiponectin levels in lean vs obese women, which would argue against adiponectin having a beneficial metabolic effect when treating beta-cells. It would be useful to provide some further comments on this possible discrepancy.
- Figure 4E compares different amounts of glucose with either FBS or no serum+adiponectin. Another condition with only no serum + vehicle for adiponectin should be included as a negative control, as shown in Figure 5.
Minor comments
- Abstract - Please specify in which model (cell/islet culture) the effects are observed.
- Sex-specific differences - The findings in humans are really interesting. However, only male rats are reported in this manuscript. Would there be any difference between male and female CR-rats sera when applied to beta-cells? This experiment would be a great addition to the paper. If the experiment cannot be completed at this time, there should be a mention to this limitation in the discussion.
- Results ‘Fig. 1A shows that the animals on the CR diet gained significantly less weight over the course of 15 weeks, but did not lose mass’ - This text refers to mass, the figure legend says weight, the y axis title on the figure states body mass. Please clarify for consistency.
- Results ‘They were within the same age range (Table 1), but were clearly distinct in body mass indexes (BMI), which separated them into lean and obese groups: lean women (BMI 22 ± 0.9, Fig. 2B)’- Please clarify the reference to Figure 2B in this fragment as the figure does not report BMI.
- Results ‘these results show a clear modulatory effect of circulating blood factors on metabolic fluxes in β-cells, which are stimulated by factors present in samples from lean and female subjects.’ - It is interesting that this is only observed for females, does this suggest that there may be sex-related factors involved, instead of or in addition to diet status? Could some further comment be added as to why the effect may only be observed in females.
- Please mention in the abstract/discussion that the results are obtained from in vitro experiments using beta-cells and islet primary cultures.
- Conclusions: suggest specifying “in the blood of lean rats” in the fragment that states “... in the blood of lean animals”.
Methods
- Please report the method of euthanasia.
- ‘experiments were carried out in accordance with the A. C. Camargo Cancer Center Institutional Review Board under registration n°. 3117/21’ - Please clarify whether the study received ethical approval, or was exempt from this requirement at this setting.
- Please report what type of fetal bovine serum (FBS) was used (e.g., charcoal-stripped FBS) as well as the FBS catalog number.
- ‘sera from both groups were collected to be used on cultured INS-1E β-cells, under physiologically relevant conditions’- Please provide further clarification on the conditions applied.
- ‘adiponectin supplementation in the plasma from obese donors’- Please report how this was prepared.
- ‘Data were expressed as means ± standard error of the mean (SEM)’ - There is a concern about using SEM to illustrate the distribution of data points, please consider using SD.
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