Brown adipocytes can display a mammary basal myoepithelial cell phenotype in vivo

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13030000) and the CAS-Novonordisk Foundation, as well as grants from the ‘1000 talents’ recruitment program, and a ‘Great-wall professorship’ from the CAS-Novonordisk Foundation all to JRS. We are grateful to all the members of Molecular Energetics Group for their support and discussion of the results. We would like to thank the Center for Biological Imaging from Institute of Biophysics Chinese Academy of Sciences and Professor Zhaohui Wang's Lab from Institute of Genetics and Developmental Biology Chinese Academy of Sciences for confocal microscopy and the Center for Developmental Biology from Institute of Genetics and Developmental Biology Chinese Academy of Sciences and Dr. Jai from Core Facility for Protein Research from Institute of Biophysics Chinese Academy of Sciences for flow cytometry. We are grateful to Dr. Kuang from Purdue University and Dr. Zhu from Chinese Academy of Medical Sciences Peking Union Medical College for the kind donation of Myf5-Cre mice and Dr. Wolfrum from the Institute of Food Nutrition and Health at the ETH Zurich for the kind donation of the Ucp1-DTR mice. Xun Huang provided valuable comments on previous versions of the manuscript.Peer reviewedPublisher PD

Analysis of Infant Microbiota Composition and the Relationship With Breast Milk Components in the Asian Elephant (Elephas Maximus) at the Zoo

The prevention of diseases through health control is essential at zoos. Here, we investigated the gut microbiota formation during infancy in an Asian elephant and compared the composition between infant and mother. Besides, we analyzed the components of breast milk and examined the correlation with the infant gut microbiota. Analysis revealed the gut microbiota of the infant contained high amount of Lactobacillales and its diversity was relatively low compared to that of the mother. We found several milk components, showed a positive correlation with the change of Lactobacillales. The present study revealed the mechanism of gut microbiota formation during infancy in an Asian elephant and provides important insights into the health control of Asian elephants in zoos

Microbiota Depletion Impairs Thermogenesis of Brown Adipose Tissue and Browning of White Adipose Tissue

This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13030000) and Natural Science Foundation of China (NSFC; 91649108), the Chinese Academy of Sciences-Novo Nordisk Foundation, as well as grants from the Chinese Academy of Sciences “1000 Talents” recruitment program and a “Great-Wall Professorship” from the Chinese Academy of Sciences-Novo Nordisk Foundation. J.R.S. was also supported by a Wolfson merit professorship from The UK Royal Society. We are grateful to all of the members of the Molecular Energetics Group for their support and discussion of the results. We would like to thank Dr. Jia and Dr. Sun from the Core Facility for Protein Research from the Institute of Biophysics, Chinese Academy of Sciences for flow cytometry, and Peter Thomson and Marina Samatiou for technical assistance with the DLW measurements.Peer reviewedPublisher PD

DJ-1 maintains energy and glucose homeostasis by regulating the function of brown adipose tissue

We thank the members of the Yuan laboratory for critical reading of the manuscript and helpful discussion. We thank the Pathology Core Facility in the Institute of Biophysics, CAS. We also thank Dr Joyce Flemmings for the English editing. This work was supported by the grants from the strategic priority research program (XDB13030000 to WJ), the National Science Foundation of China (Grant No. 81125010 and 81030025 to ZY), the National Basic Research Program of China (973–2012CB910701 and 2013DFA31990 to ZY) and Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014–2016) from Chinese Academy of Sciences; and Key research program (KJZD-EW-L01-3 to WJ), One Hundred Talents Program (WJ) of the Chinese Academy of Sciences and from the Ministry of Science and Technology of China (2012CBA01301 and 2012CB944701 to WJ), as well as by a grant from the National Natural Science Foundation of China (31171131 and 81370951 to WJ).Peer reviewedPublisher PD

Hippocampal metabolism of amino acids by L-amino acid oxidase is involved in fear learning and memory

Amino acids participate directly and indirectly in many important biochemical functions in the brain. We focused on one amino acid metabolic enzyme, L-amino acid oxidase (LAO), and investigated the importance of LAO in brain function using LAO1 knockout (KO) mice. Compared to wild-type mice, LAO1 KO mice exhibited impaired fear learning and memory function in a passive avoidance test. This impairment in LAO1 KO mice coincided with significantly reduced hippocampal acetylcholine levels compared to wild-type mice, while treatment with donepezil, a reversible acetylcholine esterase inhibitor, inhibited this reduction. Metabolomic analysis revealed that knocking out LAO1 affected amino acid metabolism (mainly of phenylalanine [Phe]) in the hippocampus. Specifically, Phe levels were elevated in LAO1 KO mice, while phenylpyruvic acid (metabolite of Phe produced largely by LAO) levels were reduced. Moreover, knocking out LAO1 decreased hippocampal mRNA levels of pyruvate kinase, the enzymatic activity of which is known to be inhibited by Phe. Based on our findings, we propose that LAO1 KO mice exhibited impaired fear learning and memory owing to low hippocampal acetylcholine levels. Furthermore, we speculate that hippocampal Phe metabolism is an important physiological mechanism related to glycolysis and may underlie cognitive impairments, including those observed in Alzheimer’s disease

CRISPRa system activates myokines FGF21 and FNDC5: Promoting fat browning and improving diet‐induced obesity in mice

Abstract Obesity causes metabolic disorders and is one of the important risk factors for diabetes. Myokines are widely involved in lipid metabolism through autocrine, paracrine and endocrine actions. FGF21 and Irisin, as representative myokines, can promote the browning of adipocytes and are potential targets for the treatment of obesity. This commentary discusses the research by Zhu et al. published in Clinical and Translational Medicine. In this study, the expression of FGF21 and FNDC5 is simultaneously activated by the CRISPRa system in vivo and in vitro. In vitro, the cell culture supernatant of C2C12 cells activated by the CRISPRa system significantly promoted the differentiation and browning of 3T3‐L1 cells; in vivo, injecting of AAV9‐dCas9‐VP64 virus could significantly reduce the body weight and fat mass of DIO mice due to an increase in browning of adipocytes

The Role of ATF-2 Family Transcription Factors in Adipocyte Differentiation: Antiobesity Effects of p38 Inhibitors▿

ATF-2 is a member of the ATF/CREB family of transcription factors and is activated by stress-activated protein kinases, such as p38. To analyze the physiological role of ATF-2 family transcription factors, we have generated mice with mutations in Atf-2 and Cre-bpa, an Atf-2-related gene. The trans-heterozygotes of both mutants were lean and had reduced white adipose tissue (WAT). ATF-2 and CRE-BPa were required for bone morphogenetic protein 2 (BMP-2)-and p38-dependent induction of peroxisome proliferator-activated receptor γ2 (PPARγ2), a key transcription factor mediating adipocyte differentiation. Since stored fat supplies have been recognized as a possible target for antiobesity treatments, we tested whether inhibition of the p38-ATF-2 pathway suppresses adipocyte differentiation and leads to reduced WAT by treating mice with a p38 inhibitor for long periods of time. High-fat diet (HFD)-induced obesity was significantly reduced in mice fed the p38 inhibitor. Furthermore, the p38 inhibitor alleviated HFD-induced insulin resistance. In p38 inhibitor-treated mice, macrophage infiltration into WAT was reduced and the tumor necrosis factor alpha (TNF-α) levels were lower than control mice. Thus, p38 inhibitors may provide a novel antiobesity treatment

The Engrailed-1 Gene Stimulates Brown Adipogenesis

As a thermogenic organ, brown adipose tissue (BAT) has received a great attention in treating obesity and related diseases. It has been reported that brown adipocyte was derived from engrailed-1 (EN1) positive central dermomyotome. However, functions of EN1 in brown adipogenesis are largely unknown. Here we demonstrated that EN1 overexpression increased while EN1 knockdown decreased lipid accumulation and the expressions of key adipogenic genes including PPARγ2 and C/EBPα and mitochondrial OXPHOS as well as BAT specific marker UCP1. Taken together, our findings clearly indicate that EN1 is a positive regulator of brown adipogenesis

Compensatory Response by Late Embryonic Tubular Epithelium to the Reduction in Pancreatic Progenitors

Early in pancreatic development, epithelial cells of pancreatic buds function as primary multipotent progenitor cells (1°MPC) that specify all three pancreatic cell lineages, i.e., endocrine, acinar and duct. Bipotent "Trunk" progenitors derived from 1°MPC are implicated in directly regulating the specification of endocrine progenitors. It is unclear if this specification process is initiated in the 1°MPC where some 1°MPC become competent for later specification of endocrine progenitors. Previously we reported that in Pdx1tTA/+;tetOMafA (bigenic) mice inducing expression of transcription factor MafA in Pdx1-expressing (Pdx1+) cells throughout embryonic development inhibited the proliferation and differentiation of 1°MPC cells, resulting in reduced pancreatic mass and endocrine cells by embryonic day (E) 17.5. Induction of the transgene only until E12.5 in Pdx1+ 1°MPC was sufficient for this inhibition of endocrine cells and pancreatic mass at E17.5. However, by birth (P0), as we now report, such bigenic pups had significantly increased pancreatic and endocrine volumes with endocrine clusters containing all pancreatic endocrine cell types. The increase in endocrine cells resulted from a higher proliferation of tubular epithelial cells expressing the progenitor marker Glut2 in E17.5 bigenic embryos and increased number of Neurog3-expressing cells at E19.5. A BrdU-labeling study demonstrated that inhibiting proliferation of 1°MPC by forced MafA-expression did not lead to retention of those progenitors in E17.5 tubular epithelium. Our data suggest that the forced MafA expression in the 1°MPC inhibits their competency to specify endocrine progenitors only until E17.5, and after that compensatory proliferation of tubular epithelium gives rise to a distinct pool of endocrine progenitors. Thus, these bigenic mice provide a novel way to characterize the competency of 1°MPC for their ability to specify endocrine progenitors, a critical limitation in our understanding of endocrine differentiation