Biology subjects

Aquilano, K.

Publications and source records attributed to Aquilano, K..

3 recordsLinked to original sources

bioRxiv2024

MACanalyzeR: scRNA-seq Analysis Tool Reveals PPARγHI Lipid-Associated Macrophages Facilitate Thermogenic Expansion in BAT

Macrophages in brown adipose tissue (BAT) play a complex role in regulating its activity. However, the role of macrophages in regulating BAT activation/deactivation has not yet been comprehensively characterized. To elucidate this, we developed MACanalyzeR, a scRNAseq-based tool specifically designed to explore the macrophage features at molecular and metabolic level. MACanalyzeR was applied in scRNA-seq datasets obtained from BAT with thermogenic loss (db/db mice) and activation (High Fat Diet, HFD). Our computational approach revealed that macrophages accumulating in BAT upon these conditions resemble lipid-associated macrophages (LAMs) with foaming-like features. BAT LAMs also show a significant enrichment of genes associated with mitochondria and lysosomes. Interestingly, LAMs identified in BAT from HFD mice positively correlate with thermogenic genes and exhibit an enrichment in PPAR{gamma} signaling pathway, with an activated mitochondrial metabolism. Cell dynamic strategy, revealed that LAM with high Pparg expression levels (PpargHIGH) progressively accumulate during skeletal muscle regeneration, suggesting a potential role for this LAM subcluster in maintaining tissue homeostasis. Our findings suggest PpargHIGH LAMs as a subclass of macrophages potentially contributing in preserving tissue homeostasis associated with high energy demand conditions such as thermogenic and regenerative stimuli.

physiology↗

bioRxiv2020

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue

Low-protein/high-carbohydrate (LPHC) diet promotes metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1- and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.

physiology↗

bioRxiv2019

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

Decreased expression of the mitochondrial protein frataxin (FXN) causes Friedreichs ataxia (FRDA). FRDA is a neurodegenerative disease also characterized by systemic metabolic alterations that increase the risk of developing type 2 diabetes thus aggravating FRDA prognosis. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that, in addition to its thermoregulatory role, turns excess energy into heat to maintain energy balance. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows reduced energy expenditure and VO2, hyperlipidemia, decreased insulin sensitivity and enhanced circulating levels of leptin, recapitulating diabetes-like signatures. FXN deficiency leads to alteration of mitochondrial structure and oxygen consumption, decreased lipolysis and lipid accumulation in BAT. Transcriptomic data highlighted a blunted thermogenesis response, as several biological processes related to thermogenesis (e.g. response to temperature stimuli, mitochondrial gene transcription, triglyceride metabolism, adipogenesis) resulted affected in BAT of KIKO mice upon cold exposure. Decreased adaptation to cool temperature in association with limited PKA-mediated lipolysis and downregulation of the expression of the genes controlling mitochondrial metabolism and lipid catabolism were observed in KIKO mice. T37i brown adipocytes and primary adipocytes with FXN deficiency showed reduced thermogenesis and adipogenesis markers respectively recapitulating the molecular signatures detected in KIKO mice.\n\nCollectively our data point to BAT dysfunction in FRDA and suggest BAT as a promising target to overcome metabolic complications in FRDA.

pathology↗