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Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice
Felipe C G Reis1, Jéssica L O Branquinho1, Bruna B Brandão1
1Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
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.
Insights
Dietary restriction prevents aging-related type 2 diabetes by maintaining Dicer levels in fat tissue. Fat-specific Dicer knockout mice show accelerated insulin resistance and mortality, highlighting Dicer's crucial metabolic role.
Area of Science:
- Metabolomics
- Molecular Biology
- Aging Research
Background:
- Aging increases type 2 diabetes risk, often preventable by dietary restriction (DR).
- DR inhibits age-related downregulation of microRNAs (miRNAs) and Dicer in white adipose tissue (WAT).
- The specific role of adipose tissue Dicer in aging and DR remains unclear.
Purpose of the Study:
- To investigate the contribution of adipose tissue Dicer to metabolic changes during aging and DR.
- To elucidate the mechanisms linking adipose tissue Dicer to insulin resistance and mortality.
Main Methods:
- Utilized fat-specific Dicer knockout (AdicerKO) mice and Lox control littermates.
- Analyzed serum metabolomics, WAT oxidative metabolism, lactate levels, and mitochondrial structure/function.
- Assessed mTORC1 activation in WAT and skeletal muscle, insulin sensitivity, and mortality rates.
- Investigated the effect of rapamycin on insulin resistance in AdicerKO mice.
Main Results:
- AdicerKO mice exhibited distinct serum metabolite profiles, with elevated branched-chain amino acids (BCAA).
- Reduced oxidative metabolism, increased lactate, and altered mitochondrial function were observed in WAT of AdicerKO mice.
- AdicerKO mice showed increased mTORC1 activation, accelerated insulin resistance, and premature mortality.
- DR-induced insulin sensitivity was lost in AdicerKO mice but restored by rapamycin, indicating mTORC1-driven insulin resistance.
Conclusions:
- Adipose tissue Dicer plays a critical, DR-modulated role in controlling metabolism and insulin sensitivity during aging.
- Dicer in WAT is essential for preventing age-associated metabolic dysfunction and mortality.
- mTORC1 hyperactivation in AdicerKO mice drives insulin resistance, independent of Dicer levels in skeletal muscle.
