bims-mimead 2024-10-20 papers

bims-mimead

Biomed News

on Mitochondrial metabolism in ageing and metabolic disease

Issue of 2024–10–20
ten papers selected by
Rachel M. Handy, University of Guelph

Impacts of time-restricted feeding on middle-aged and old mice with obesity.
Molecular mechanisms of mitochondrial dynamics.
Low-intensity pulsed ultrasound improves metabolic dysregulation in obese mice by suppressing inflammation and extracellular matrix remodeling.
Impaired Suppression of Plasma Lipid Extraction and its Partitioning Away from Muscle by Insulin in Humans with Obesity.
Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance.
Antioxidant mito-TEMPO prevents the increase in tropomyosin oxidation and mitochondrial calcium accumulation under 7-day rat hindlimb suspension.
The SIRT5-Mediated Upregulation of C/EBPβ Promotes White Adipose Tissue Browning by Enhancing UCP1 Signaling.
Decoding visceral adipose tissue molecular signatures in obesity and insulin resistance: a multi-omics approach.
Depot-specific mRNA expression programs in human adipocytes suggest physiological specialization via distinct developmental programs.
The translation initiation factor eIF2α regulates lipid homeostasis and metabolic aging.

J Physiol. 2024 Oct 15.

Impacts of time-restricted feeding on middle-aged and old mice with obesity.

Yueze Yang, Dexi Liu.

  Time-restricted feeding is known to ameliorate obesity in young mice. However, evaluation of its effect in old age is still lacking. The current work aims to investigate the effects of time-restricted feeding on treating pre-existing obesity in old animals. The study utilized middle-aged and old high fat diet-induced obese mice and subjected them to 8 h daily time-restricted feeding. Aged obese mice did not lose fat mass but lost lean mass after 8 weeks of treatment. In addition, time-restricted feeding reduced adiposity in brown adipose tissue, reversed excessive hepatic lipid accumulation, and improved glucose homeostasis in middle-aged and old obese mice. Mechanistic studies show that these metabolic benefits were mediated by transcriptional downregulation of essential genes responsible for hepatic adipogenesis and adipose tissue chronic inflammation. These results demonstrate that time-restricted feeding improves metabolic health and has beneficial effects in combating diet-induced obesity in aged obese mice. KEY POINTS: Contrary to in young obese mice, in old obese mice time-restricted feeding did not significantly reduce body fat but decreased lean mass. Time-restricted feeding reduced adipose tissue inflammation, reversed fatty liver, and improved glucose homeostasis in aged mice with diet-induced obesity. Time-restricted feeding is effective in improving metabolic homeostasis in aged mice, but less effective in terms of reducing obesity. Future studies should investigate the underlying mechanism of how ageing impaired intermittent fasting induced fat loss.

Keywords:  ageing; fatty liver; insulin resistance; intermittent fasting; obesity; time‐restricted feeding

DOI:  https://doi.org/10.1113/JP285462
Nat Rev Mol Cell Biol. 2024 Oct 17.

Molecular mechanisms of mitochondrial dynamics.

Luis-Carlos Tábara, Mayuko Segawa, Julien Prudent.

Mitochondria not only synthesize energy required for cellular functions but are also involved in numerous cellular pathways including apoptosis, calcium homoeostasis, inflammation and immunity. Mitochondria are dynamic organelles that undergo cycles of fission and fusion, and these transitions between fragmented and hyperfused networks ensure mitochondrial function, enabling adaptations to metabolic changes or cellular stress. Defects in mitochondrial morphology have been associated with numerous diseases, highlighting the importance of elucidating the molecular mechanisms regulating mitochondrial morphology. Here, we discuss recent structural insights into the assembly and mechanism of action of the core mitochondrial dynamics proteins, such as the dynamin-related protein 1 (DRP1) that controls division, and the mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1) driving membrane fusion. Furthermore, we provide an updated view of the complex interplay between different proteins, lipids and organelles during the processes of mitochondrial membrane fusion and fission. Overall, we aim to present a valuable framework reflecting current perspectives on how mitochondrial membrane remodelling is regulated.

DOI: https://doi.org/10.1038/s41580-024-00785-1
Ultrasonics. 2024 Oct 10. pii: S0041-624X(24)00251-8. [Epub ahead of print]145 107488

Low-intensity pulsed ultrasound improves metabolic dysregulation in obese mice by suppressing inflammation and extracellular matrix remodeling.

Min He, Hong Zhu, Jingsong Dong, Wenzhen Lin, Boyi Li, Ying Li, Dean Ta.

  Chronic inflammation in white adipose tissue is crucial in obesity and related metabolic disorders. Low-intensity pulsed ultrasound (LIPUS) is renowned for its anti-inflammatory effects as a non-invasive treatment, yet its precise role in obesity has been uncertain. Our study investigates the therapeutic effect of LIPUS and its underlying mechanism on obesity in mice, thereby offering a novel approach for non-invasive treatment of obesity and associated metabolic disorders for human. Male C57BL/6J mice aged 10 weeks were fed a high-fat diet (HFD) for 8 weeks to establish obesity model, then underwent 8 weeks of LIPUS (frequency: 1.0 MHz, duty cycle: 20 %, Isata: 58-61 mW/cm2, 20 min per day) stimulation of the epididymal white adipose tissue. Fat and lean mass were measured using nuclear magnetic resonance (NMR), while energy homeostasis was evaluated using metabolic cages. Insulin resistance was assessed using glucose tolerance tests (GTT) and insulin tolerance tests (ITT). Regulatory mechanisms were explored using RNA sequencing. Results showed that LIPUS significantly reduced obesity markers in obese mice, including body and adipose tissue weight, and improved insulin resistance, without affecting food intake. RNA sequencing showed 250 up-regulated and 351 down-regulated genes between HFD-LIPUS group and HFD-Sham group, suggesting anti-inflammatory action. Quantitative PCR confirmed reduced pro-inflammatory gene expression and macrophage infiltration in eWAT. Gene set enrichment analysis showed decreased NF-κB signaling and extracellular matrix-receptor interactions in LIPUS-treated mice. Thus, LIPUS effectively mitigates metabolic dysregulation in HFD-induced obesity through inflammation suppression and extracellular matrix remodeling, which provides a potential physical therapy for metabolic syndrome in clinic.

Keywords:  Adipose tissue; Inflammation; Insulin resistance; LIPUS; Obesity

DOI:  https://doi.org/10.1016/j.ultras.2024.107488
J Clin Endocrinol Metab. 2024 Oct 14. pii: dgae727. [Epub ahead of print]

Impaired Suppression of Plasma Lipid Extraction and its Partitioning Away from Muscle by Insulin in Humans with Obesity.

Christos S Katsanos, Lee Tran, Nyssa Hoffman, Lori R Roust, Eleanna De Filippis, Lawrence J Mandarino, Kailin Johnsson, Marek Belohlavek, Matthew R Buras.

   CONTEXT: Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown.
OBJECTIVE: We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and non-esterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR).
METHODS: The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat.
RESULTS: Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous, but not ingested, origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects.
CONCLUSIONS: Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.

Keywords:  forearm; insulin resistance; muscle; obesity; stable isotopes; triglycerides

DOI:  https://doi.org/10.1210/clinem/dgae727
Diabetologia. 2024 Oct 18.

Circulating extracellular vesicle-carried PTP1B and PP2A phosphatases as regulators of insulin resistance.

Metabol Study Group

   AIMS/HYPOTHESIS: Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications.
METHODS: Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells.
RESULTS: Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes.
CONCLUSIONS/INTERPRETATION: These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity.

Keywords:  Adipose tissue; Extracellular vesicles; Insulin resistance; Liver; Phosphatases

DOI:  https://doi.org/10.1007/s00125-024-06288-0
Free Radic Biol Med. 2024 Oct 13. pii: S0891-5849(24)00987-0. [Epub ahead of print]224 822-830

Antioxidant mito-TEMPO prevents the increase in tropomyosin oxidation and mitochondrial calcium accumulation under 7-day rat hindlimb suspension.

Daria A Sidorenko, Gleb V Galkin, Roman O Bokov, Ekaterina A Tyrina, Natalia A Vilchinskaya, Irina D Lvova, Sergey A Tyganov, Boris S Shenkman, Kristina A Sharlo.

  After the first day of muscle disuse (unloading) mitochondria-derived ROS accumulate in the postural-tonic soleus muscle. It is known that excess of ROS can lead to the accumulation of intramitochondrial calcium and overload of mitochondria with calcium, can negatively affect mitochondrial function and fatigue resistance of soleus muscle. We assumed that the use of mitochondrial ROS scavenger mito-TEMPO will be able to prevent the unloading-induced disruption of mitochondrial functions and will help maintain soleus muscle fatigue resistance. To test this hypothesis, male rats were divided into 3 groups (n = 16 in each): vivarium control with placebo (C), 7-day hindlimb suspension with placebo (7HS) and 7-day hindlimb suspension with intraperitoneal administration of the mimetic superoxide dismutase mito-TEMPO at a dose of 1 mg/kg (7HSM). In the 7HS group, increased fatigue of the soleus muscle was found in the ex vivo test, accompanied with increased activity of ETC complex I and "leak" respiration, as well as a twofold increased content of oxidized tropomyosin (a marker of ROS level in tissues) and increase in intramitochondrial calcium compared to C. In 7HSM, the activity of ETC complex I and "leak" respiration had no significant differences from the control group, and the increase in intramitochondrial calcium and the content of oxidized tropomyosin was partially prevented, however, muscle fatigue was also significantly higher than in the control group. Thus, mitochondrial ROS under 7-day muscle unloading contribute to the accumulation of intramitochondrial calcium and oxidation of tropomyosin, but do not have a significant effect on soleus muscle function.

Keywords:  Atrophy; Calcium; Mitochondria; Muscle disuse

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.285
Int J Mol Sci. 2024 Sep 29. pii: 10514. [Epub ahead of print]25(19):

The SIRT5-Mediated Upregulation of C/EBPβ Promotes White Adipose Tissue Browning by Enhancing UCP1 Signaling.

Xiangyun Zhai, Liping Dang, Shiyu Wang, Chao Sun.

  Sirtuin 5 (SIRT5) plays an important role in the maintenance of lipid metabolism and in white adipose tissue browning. In this study, we established a mouse model for diet-induced obesity and the browning of white fat; combined with gene expression intervention, transcriptome sequencing, and cell molecular biology methods, the regulation and molecular mechanisms of SIRT5 on fat deposition and beige fat formation were studied. The results showed that the loss of SIRT5 in obese mice exacerbated white adipose tissue deposition and metabolic inflexibility. Furthermore, the deletion of SIRT5 in a white-fat-browning mouse increased the succinylation of uncoupling protein 1 (UCP1), resulting in a loss of the beiging capacity of the subcutaneous white adipose tissue and impaired cold tolerance. Mechanistically, the inhibition of SIRT5 results in impaired CCAAT/enhancer binding protein beta (C/EBPβ) expression in brown adipocytes, which in turn reduces the UCP1 transcriptional pathway. Thus, the transcription of UCP1 mediated by the SIRT5-C/EBPβ axis is critical in regulating energy balance and obesity-related metabolism.

Keywords:  SIRT5; UCP1; fat synthesis; protein succinylation; white adipose tissue browning

DOI:  https://doi.org/10.3390/ijms251910514
Obesity (Silver Spring). 2024 Oct 13.

Decoding visceral adipose tissue molecular signatures in obesity and insulin resistance: a multi-omics approach.

Dipayan Roy, Raghumoy Ghosh, Ritwik Ghosh, Manoj Khokhar, Ma Yin Yin Naing, Julián Benito-León.

OBJECTIVE: Obesity-associated insulin resistance (IR) is responsible for considerable morbidity and mortality globally. Despite vast genomic data, many areas, from pathogenesis to management, still have significant knowledge gaps. We aimed to characterize visceral adipose tissue (VAT) in obesity and IR through a multi-omics approach.
METHODS: We procured data on VAT samples from the Gene Expression Omnibus (GEO) for the following two groups: 1) populations with obesity (n = 34) versus those without (n = 26); and 2) populations with obesity and IR (n = 15) versus those with obesity but without IR (n = 15). Gene set enrichment, protein-protein interaction network construction, hub gene identification, and drug-gene interactions were performed, followed by regulatory network prediction involving transcription factors (TFs) and microRNAs (miRNAs).
RESULTS: Interleukin signaling pathways, cellular differentiation, and regulation of immune response revealed a significant cross talk between VAT and the immune system. Other findings include cancer pathways, neurotrophin signaling, and aging. A total of 10 hub genes, i.e., STAT1, KLF4, DUSP1, EGR1, FOS, JUN, IL2, IL6, MMP9, and FGF9, 24 TFs, and approved hub gene-targeting drugs were obtained. A total of 10 targeting miRNAs (e.g., hsa-miR-155-5p, hsa-miR-34a-5p) were associated with obesity and IR-related pathways.
CONCLUSIONS: Our multi-omics integration method revealed hub genes, TFs, and miRNAs that can be potential targets for investigation in VAT-related inflammatory processes and IR, therapeutic management, and risk stratifications.

DOI: https://doi.org/10.1002/oby.24146
PLoS One. 2024 ;19(10): e0311751

Depot-specific mRNA expression programs in human adipocytes suggest physiological specialization via distinct developmental programs.

Heather J Clemons, Daniel J Hogan, Patrick O Brown.

Adipose tissue is distributed in diverse locations throughout the human body. Not much is known about the extent to which anatomically distinct adipose depots are functionally distinct, specialized organs, nor whether depot-specific characteristics result from intrinsic developmental programs, as opposed to reversible physiological responses to differences in tissue microenvironment. We used DNA microarrays to compare mRNA expression patterns of isolated human adipocytes and cultured adipose stem cells, before and after ex vivo adipocyte differentiation, from seven anatomically diverse adipose tissue depots. Adipocytes from different depots display distinct gene expression programs, which are most closely shared with anatomically related depots. mRNAs whose expression differs between anatomically diverse groups of depots (e.g., subcutaneous vs. internal) suggest important functional specializations. These depot-specific differences in gene expression were recapitulated when adipocyte progenitor cells from each site were differentiated ex vivo, suggesting that progenitor cells from specific anatomic sites are deterministically programmed to differentiate into depot-specific adipocytes. Many developmental transcription factors show striking depot-specific patterns of expression, suggesting that adipocytes in each anatomic depot are programmed during early development in concert with anatomically related tissues and organs. Our results support the hypothesis that adipocytes from different depots are functionally distinct and that their depot-specific specialization reflects distinct developmental programs.

DOI: https://doi.org/10.1371/journal.pone.0311751
Aging Cell. 2024 Oct 15. e14348

The translation initiation factor eIF2α regulates lipid homeostasis and metabolic aging.

Haipeng Huang, Yilie Liao, Ning Li, Xingfan Qu, Chaocan Li, Jiaqi Hou.

  Aging is usually accompanied by excessive body fat gain, leading to increased susceptibility to comorbidities. This study aimed to explore an unexpected function for the eukaryotic initiation factor-2α (eIF2α) during aging. Reducing the eIF2α dose led to a reconfiguration of the metabolic equilibrium, promoting catabolism, facilitating lipolysis, and decreasing body fat accumulation while maintaining healthy glucose and lipid metabolism during aging. Specifically, eIF2α enhanced the expression of distinct messenger RNAs encoding mitochondrial electron transport chain proteins at the translation level. The mitochondrial respiration increased in eIF2α heterozygotes, even during aging. Deceleration of translation was demonstrated as a conserved mechanism for promoting longevity across various species. Our findings demonstrated that the restriction of translation by reducing eIF2α expression could fend off multiple tissue damage and improve metabolic homeostasis during aging. Hence, eIF2α was a crucial target for benefiting mammalian aging achieving delayed mammalian aging.

Keywords:  ISR; aging; eIF2α; lipid metabolism; mitochondria; translation

DOI:  https://doi.org/10.1111/acel.14348