Adiponectin exerts sex-dependent effects on lipid, amino acid, and glucose metabolism during caloric restriction

  1. Yoshiko M Ikushima
  2. Kuan-Chan Chen
  3. Richard J. Sulston
  4. Domenico Mattiucci
  5. Eleanor J. Brain
  6. Stefanie A Fung Xin Zi
  7. Karla J. Suchacki
  8. Benjamin J. Thomas
  9. Andrea Lovdel
  10. Matthew Bennett
  11. Hiroshi Kobayashi
  12. Phillip D. Whitfield
  13. Keiyo Takubo
  14. Andrew H. Baker
  15. Nicholas M. Morton
  16. Robert K. Semple
  17. William P. Cawthorn

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Abstract

Adiponectin is the most abundant hormone in the circulation. Plasma adiponectin decreases in obesity but increases in leanness, including during caloric restriction (CR) in animals and humans. In obesity, adiponectin deficiency promotes cardiometabolic dysfunction. In contrast, the roles of adiponectin in CR, when it is at its highest, are largely unknown. To address this, we studied global adiponectin knockout (KO) in male and female mice fed either ad libitum (AL) or a 30% CR diet from 9-13 weeks of age. We show that adiponectin KO did not alter CR effects on body mass, body composition, or energy expenditure. However, KO unexpectedly decreased blood glucose levels during CR, both on fasting and following an oral glucose challenge. This is opposite to the effects of adiponectin deficiency in the context of ad libitum diet (AL) or obesity, and occurred without changes in insulin secretion or sensitivity. Moreover, adiponectin KO augmented CR-induced increases in plasma fatty acids in both sexes and, in males only, impaired systemic triglyceride clearance under CR. Indirect calorimetry further revealed that adiponectin KO alters the shifts between carbohydrate and lipid utilisation that occur during transitions between fed and fasted states. To determine potential molecular mechanisms, we investigated effects of adiponectin KO on the liver, a major adiponectin target that plays key roles entraining metabolism to nutritional state. Hepatic transcriptomics revealed that, in both sexes, adiponectin KO upregulates sterol and fatty acid synthesis genes under AL while increasing amino acid catabolic genes during CR. Together, our findings suggest that adiponectin tunes glucose, lipid, and amino acid metabolism during CR, in whole or in part through effects on the liver. The widely reported functions of adiponectin in pathological states, including obesity and insulin resistance, thus differ sharply from its roles during CR, with marked sexual dimorphism apparent for many of these functions.

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    SUMMARY

    This manuscript investigates the physiological role of adiponectin, particularly its importance for metabolic adaptation during caloric restriction (CR), an area of research with significant implications for understanding healthspan and longevity. Expanding on a previous elegant study where they uncovered sexual dimorphism in the response to CR in mice, the authors employed here in vivo models using adiponectin knockout (KO) mice and wild-type controls, subjecting them to a 30% CR diet and assessing changes in body weight, energy expenditure, and glucose, lipid, and amino acid metabolism, with a focus on hepatic effects and sex differences. Interestingly, the study found that adiponectin is not required for CR-induced weight loss, body composition changes, or alterations in energy expenditure and respiratory exchange ratio. However, the research highlights a crucial role for adiponectin in fine-tuning glucose, lipid, and amino acid metabolism during CR, potentially through its influence on the liver. Specifically, the adiponectin KO group exhibited greater glucose lowering during CR and altered substrate utilization during the feeding-fasting transition, accompanied by transcriptional changes indicative of altered amino acid catabolism in the liver. This work offers valuable insights into the complex role of adiponectin in metabolic adaptation to CR and opens avenues for future research exploring the underlying mechanisms and potential therapeutic implications. We liked the approach of the authors to investigate this important hormone, and we consider this a very robust study with data that sustains the main conclusions of the authors. We have a few questions and comments after our evaluation of the manuscript.

    Major comments

    The selection of proper controls is very important to obtain reproducible and reliable results. While the number of mice and the inclusion of both sexes in this study likely yields robust results, we have a few questions related to the selection of diet and feeding window in this study.

    Instead of reducing the amount of food given to CR mice, the authors used a different diet for CR mice. As we understand it, this CR diet has the same macronutrient composition as the one used for AL feeding but different energy density, so when providing the same amount of food to AL mice and CR mice, CR mice will have 30% less energy intake. While this interpretation can be extracted from the manuscript, we think it may not be clear to all readers. Therefore, a bit more clarification on this aspect would improve the understanding of the experimental design. For example, did authors provide the same amount of food to CR and AL mice, and therefore after 24 hours, there is no more food in the cage for both groups? Do CR mice take less time to eat that same amount of food than AL mice? One can assume this is true after looking at post-prandial RER, which increases faster in CR mice. Visualizing food intake measurements would help to interpret these data.

    We have a similar comment related to the feeding window of the mice. We can read in the manuscript that food was provided at 10.30 am. We assume this applies to both groups of mice (AL and CR), but again is not 100% clear in the method's description, as the authors only refer to CR mice when talking about the time when food was introduced. In addition, when one looks at RER, it seems that AL mice had normal circadian rhythms, as RER increases around 6pm. Why was this 10:30 am time selected? We are sure there is a specific reason for this but we would like to see it in the manuscript, as one could wonder the effect this feeding window might have on mice that usually eat during the dark phase. Have you considered how the timing of food availability might influence circadian rhythm-dependent metabolic responses?. We are thinking of something like the authors already did in Table 1 in the previous Elife paper where they described sexual dimorphism in the response to CR, and the groups and conditions are clearly described. An expanded discussion on this alteration in circadian rhythms imposed by the intervention would be beneficial for the manuscript.

    Minor comments

    We found fascinating the reported differences between WT and adiponectin KO mice and the sexual dimorphism found when subjecting these mice to CR. The changes found in adiponectin KO CR mice somehow resemble the metabolic changes found in mice with a defect in fatty acid oxidation after fasting, such as hypoglycemia and reliance on amino acid catabolism for the obtention of energy. Have the authors investigated this metabolic pathway with a bit more detail in this context?

    Has the role of adiponectin been studied in the response to CR in diet-induced obese mice? This could be discussed, as it would shed light on differential roles of adiponectin in these conditions.

    Competing interests

    The authors declare that they have no competing interests.

  2. Version published to 10.1101/2025.01.20.633882v1 on bioRxiv