bims-aditis 2022-05-15 papers

Issue of 2022–05–15
four papers selected by
Matthew C. Sinton, University of Glasgow

Adipocyte. 2022 May 12.

Generation of functional fat organoid from rat superficial fascia.

Yanfei Zhang, Yuanyuan Zhang, Yingyue Dong, Tongsheng Chen, Guoheng Xu.

The organoid is a 3D cell architecture formed by self-organized tissues or cells in vitro with similar cell types, histological structures, and biological functions of the native organ. Depending on the unique organ structures and cell types, the production of organoids requires individualized design and is still challenging. Organoids of some organs and tissues, including adipose tissue, remain to generate to be more faithful to their original organ in structure and function. We previously established a new model of the origin of adipose cells originating from non-adipose fascia tissue. Superficial fascia has abundant preadipocytes that are capable of adipogenic differentiation and are highly active in vivo. Here, we investigated superficial fascia fragments in 3D hydrogel and found they were able to transform into relatively large adipocyte aggregates containing mature unilocular adipocytes, which were virtually "fat organoids" of adipose tissue. Such fascia-originated fat organoids had a typical structure of adipose tissues and possessed the principal function of adipose cells in the synthesis, storage, hydrolysis of triglycerides and adipokines secretion. Producing fat organoids from superficial fascia can provide a new approach for adipocyte research and has broad applications in drug screening, plastic surgery, and regenerative medicine. Most importantly, the generation of fascia-derived functional fat organoids strongly evidences that both adipose tissues and cells originate from fascia. Our findings give insights into metabolic regulation by the crosstalk between multiple different organs and tissues and provide new knowledge for investigating novel treatments for obesity, diabetes and other metabolic diseases.

Keywords: 3D hydrogel; Superficial fascia; adipogenesis; adipose tissue; fascial preadipocyte; fat organoid

DOI: https://doi.org/10.1080/21623945.2022.2072446

FASEB J. 2022 May;36 Suppl 1

Identification of Adipose-Specific iNKT Cell Subpopulation through Single-Cell RNA Sequencing.

Sang Mun Han, Jeu Park, Eun Seo Park, Yoon Ha Choi, Jin Young Huh, Jong Kyoung Kim, Jae Bum Kim.

Invariant natural killer T (iNKT) cells are innate T cells that recognize CD1d-loaded lipid antigens. In adipose tissue, iNKT cells contribute to maintenance of adipose tissue homeostasis through active communication with CD1d-positive adipocytes. By recognizing lipid antigens, adipose iNKT cells kill harmful cells, such as hypertrophic adipocytes and pro-inflammatory macrophages, and promote stem cell proliferation. These characteristics seem not to be observed in hepatic or splenic iNKT cells. However, it has not been thoroughly understood how adipose iNKT cells control cell fates in adipose tissue. Here, we adopted single-cell RNA sequencing to identify unique subpopulations of adipose iNKT cells involved in the clearance of deleterious cells or stem cell renewal. Adipose iNKT cells were largely categorized into 3 subpopulations; iNKT1A, iNKT1B, and iNKT17. Transcriptome analysis revealed that iNKT1A cells were the adipose-specific subpopulation, while iNKT1B and iNKT17 cells were similar to splenic and thymic iNKT cells. Moreover, adoptive transfer experiments showed that iNKT1A cells were generated only in adipose tissue, but not in other organs, indicating that adipose tissue microenvironment plays crucial roles for generation of iNKT1A cells. Collectively, our data showed that iNKT1A cells would be the adipose-specific iNKT subpopulation and could be generated by adipose tissue microenvironment.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.R3299

FASEB J. 2022 May;36 Suppl 1

Itaconate is a negative regulator of hepatic lipid metabolism during sepsis.

Rabina Mainali, Matthew Quinn.

Sepsis is a life-threatening clinical implication with increased uncontrolled host immune response to an infection, mortality, morbidity, and financial burden worldwide. Due to its critical role in metabolic reprogramming in inflammation, the Irg1/itaconate has received much attention as an immunomodulator. However, understanding of itaconate's anti-inflammatory and immunometabolic activities in response to infections is mostly limited to immune cells. By employing multi-omic approaches, here we show that in the context of sepsis, a disruption in TCA cycle flow drives hepatic itaconate accumulation, indicating potential non-immune functions. However, the functional role of itaconate in this central organ critical to maintaining systemic metabolism is yet to be elucidated. To gain more insight into its physiological role in the liver during sepsis, we subjected wild-type and whole-body Irg1 knockout mice to sepsis via cecal slurry injection. In conjunction with our previous findings, we find wild-type septic mice develop hepatic steatosis. Interestingly, global Irg1 knockout mice develop a more severe form of a hepatic steatotic phenotype and a significant increase in hepatic lipid burden compared to wild-type counterparts in response to sepsis. This data demonstrates itaconate as a negative regulator of hepatic lipid accumulation in the context of sepsis. However, the exact molecular mechanism by which itaconate interacts with regulators of hepatic lipid metabolism during sepsis is yet to be uncovered. As an anti-inflammatory metabolite, itaconate limits the glycolytic response in activated immune cells. Similarly, invitro, we find that 4-OI, an itaconate derivative, antagonizes LPS induced glycolysis in hepatocytes. Given our findings of heightened lipid accumulation in septic Irg1 knockout mice, we further hypothesize glycolysis to be elevated and fueling de novolipogenesis via the production of acetyl-CoA. Indeed, unbiased metabolomics data show heightened hepatic lactate levels indicative of hyperactivated glycolysis in knockout septic mice. Mechanistically, we find elevated gene and protein expression of lactate dehydrogenase, the enzyme that facilitates the conversion of pyruvate to lactate, driving this accumulation of lactate seen in septic Irg1 knockout mice. In summary, our preliminary findings thus far highlights itaconate as a negative modulator of hepatic glycolysis as well as de novo lipogenesis in restraining sepsis-induced hepatic steatosis.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.0R352

FASEB J. 2022 May;36 Suppl 1

Transcriptome profile of white, brown and beige adipose tissue.

Henry Paz, Ying Zhong, Anna-Claire Pilkington, Kartik Shankar, Umesh Wankhade.

Adipose tissue dysregulation lies at the core metabolic syndrome. White adipose tissue (WAT) has the capacity to store energy, whereas brown adipose tissue (BAT) can dissipate energy through thermogenesis. Newly discovered beige adipocytes are brown like adipocytes recruited in WAT in response to b3-adrenergic stimulation (CL316,243) or cold temperatures. Despite the important metabolic role, information regarding differential expression of molecular markers between different adipose tissue, especially beige and other depots is scarce. The objective of this study was to identify the shared and unique transcript signatures that characterize WAT, BAT and beige adipose tissue. We collected inguinal WAT (iWAT), gonadal WAT (gWAT) and BAT from male C57BL6/J mice fed a control diet (17% fat) for 13 weeks. Beige WAT (iWATCL) was isolated from mice treated with b3-adrenergic agonist CL316, 243 for 7 days (1 mg/kg BW, ip). RNA sequencing was used to generate transcriptional profiles. Using gWAT as control, differentially expressed genes (DEGs) were determined with the DEseq2 and considered when the false discovery rate corrected P-value was ≤ 0.05 and the fold change ≥ 4. Principal components analysis revealed that the transcriptional profiles differed across BAT, gWAT and iWAT and iWATCL. Across adipose tissues, 208 DEGs were shared. Between BAT and iWATCL, 223 DEGs were shared and were associated with muscle related pathways. Unique DEGs were 1130, 549, and 40 for BAT, iWAT, and iWATCL, respectively. Top upregulated unique genes included Lncbate10, Zic1, and Gm32468 in BAT; Dsc3, Cd22 and H2-M2 in iWAT; and Cacng5, Mup11 and Mup9 in iWATCL. Among other processes, genes upregulated in BAT were associated with cellular respiration and fatty acid biosynthesis, in iWAT with immune responses and in iWATCL with sodium ion homeostasis and cellular response to lipids. Overall results show transcriptional heterogeneity across adipose tissues depots, especially the unique set of transcripts in CL316, 243 induced beige adipocytes that can serve specific markers.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.R4968