Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice.

Felipe C G,William T Festuccia,Thomas Thomou,Saverio Cinti,Bruna B Brandão,C Ronald Kahn,Marcelo A Mori,Ismael D Silva,Jéssica L O,Loris Sartini,Alicia J Kowaltowski,Beatriz A Guerra,Andrea Frontini

doi:10.18632/aging.100970

Abstract

Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance.

Highlights

Aging is an important risk factor for chronic diseases such as type 2 diabetes (T2D) [1]
AdicerKO mice had larger brown adipose tissue mass and smaller epididymal mal white adipose tissue (WAT) depots when fed ad libitum (AL), as previously described [16], and these differences persisted under the Dietary restriction (DR) condition (Supplementary Fig. 1B)
AGING, May 2016, Vol 8 No.5 upregulation within 10.5-days of DR (Supplementary Fig. 4B). To test if it was the ablation of Dicer in adipocytes or the consequent age-dependent lipodystrophic phenotype of AdicerKO mice that blocked the effect of DR over mitochondrial biogenesis in WAT, we studied the effect of the regimen in young mice, before the onset of lipodystrophy [16]

Summary

Introduction

Aging is an important risk factor for chronic diseases such as type 2 diabetes (T2D) [1]. Dietary restriction (DR) increases lifespan and delays the onset of T2D in mammals, including humans [2, 3]. This is thought to be a consequence of increased insulin sensitivity and improved glucose disposal, the mechanisms underlying these effects of DR have not yet been elucidated in detail. DR has been shown to ameliorate oxidative imbalance [4] and inflammation [5, 6] in a variety of tissues, including the white adipose tissue (WAT), contributing to enhance local and whole body insulin signaling [7,8,9]. Impaired BCAA metabolism in adipose tissue and BCAA accumulation in the blood stream have been associated with T2D [13]

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Results

Conclusion