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ApoL6 is a new LD-associated protein containing an apoprotein-like domain, expressed mainly in adipose tissue, specifically in adipocytes. ApoL6 expression is low in fasting but induced upon feeding. ApoL6 knockdown results in smaller LD with lower triglyceride (TAG) content in adipocytes, while ApoL6 overexpression causes larger LD with higher TAG content. We show that ApoL6 effect in adipocytes is by inhibition of lipolysis. While ApoL6, Perilipin 1 (Plin1) and HSL can form a complex on LD, C-terminal domain of ApoL6 directly interacts with Plin1, to compete with Plin1 binding to HSL through Plin1 N-terminal domain, thereby keeping HSL in a “stand by” status. Thus, ApoL6 ablation decreases WAT mass, protecting mice from diet-induced obesity, while adipose overexpression increases WAT mass to bring obesity and insulin resistance with hepatosteatosis, making ApoL6 a potential future target against obesity and diabetes.

Adipose tissue mass and adiposity change throughout the lifespan. During aging, while visceral adipose tissue (VAT) tends to increase, peripheral subcutaneous adipose tissue (SAT) decreases significantly. Unlike VAT, which is linked to metabolic diseases, including type 2 diabetes, SAT has beneficial effects. However, the molecular details behind the aging-associated loss of SAT remain unclear. Here, by comparing scRNA-seq of total stromal vascular cells of SAT from young and aging mice, we identify an aging-dependent regulatory cell (ARC) population that emerges only in SAT of aged mice and humans. ARCs express adipose progenitor markers but lack adipogenic capacity; they secrete high levels of pro-inflammatory chemokines, including Ccl6, to inhibit proliferation and differentiation of neighboring adipose precursors. We also found Pu.1 to be a driving factor for ARC development. We identify an ARC population and its capacity to inhibit differentiation of neighboring adipose precursors, correlating with aging-associated loss of SAT.

Kings and queens of eusocial termites can live for decades, while queens sustain a nearly maximal fertility. To investigate the molecular mechanisms underlying their long lifespan, we carried out transcriptomics, lipidomics and metabolomics in Macrotermes natalensis on sterile short-lived workers, long-lived kings and five stages spanning twenty years of adult queen maturation. Reproductives share gene expression differences from workers in agreement with a reduction of several aging-related processes, involving upregulation of DNA damage repair and mitochondrial functions. Anti-oxidant gene expression is downregulated, while peroxidability of membranes in queens decreases. Against expectations, we observed an upregulated gene expression in fat bodies of reproductives of several components of the IIS pathway, including an insulin-like peptide, Ilp9. This pattern does not lead to deleterious fat storage in physogastric queens, while simple sugars dominate in their hemolymph and large amounts of resources are allocated towards oogenesis. Our findings support the notion that all processes causing aging need to be addressed simultaneously in order to prevent it., Séité, Harrison, et al. investigate the mechanisms underlying long lifespan in queens and kings of the highly social termite Macrotermes natalensis. Using transcriptomics, lipidomics and metabolomics, this study shows that several aging-related processes are reduced in the fat bodies of these reproductives and that an upregulated insulin-like peptide, Ilp9, does not lead to deleterious fat storage in old queens, while simple sugars dominate in their hemolymph.

SUMMARY Brown adipose tissue harbors UCP1 to dissipate chemical energy as heat. However, the transcriptional network that governs the thermogenic gene program is incompletely understood. Zc3h10, a CCCH-type zinc finger protein, has recently been reported to bind RNA. However, we report here that Zc3h10 functions as a transcription factor to activate UCP1 not through the enhancer region, but by binding to a far upstream region of the UCP1 promoter. Upon sympathetic stimulation, Zc3h10 is phosphorylated at S126 by p38 mitogen-activated protein kinase (MAPK) to increase binding to the distal region of the UCP1 promoter. Zc3h10, as well as mutant Zc3h10, which cannot bind RNA, enhances thermogenic capacity and energy expenditure, protecting mice from diet-induced obesity. Conversely, Zc3h10 ablation in UCP1+ cells in mice impairs thermogenic capacity and lowers oxygen consumption, leading to weight gain. Hence, Zc3h10 plays a critical role in the thermogenic gene program and may present future targets for obesity therapeutics., Graphical Abstract, In Brief Zc3h10 is a RNA-binding protein. Here, Yi et al. report Zc3h10 is a transcription factor that activates UCP1 and other BAT genes. Cold/β3 stimulation causes phosphorylation of Zc3h10 at S126 by p38 MAPK to increase its binding to targets genes and, thus, promotes thermogenic capacity and energy expenditure.

The mammary gland experiences substantial remodeling and regeneration during development and reproductive life, facilitated by stem cells and progenitors that act in concert with physiological stimuli. While studies have focused on deciphering regenerative cells within the parenchymal epithelium, cell lineages in the stroma that may directly contribute to epithelial biology is unknown. Here we identify, in mouse, the transition of a PDGFRα+ mesenchymal cell population into mammary epithelial progenitors. In addition to being adipocyte progenitors, PDGFRα+ cells make a de novo contribution to luminal and basal epithelia during mammary morphogenesis. In the adult, this mesenchymal lineage primarily generates luminal progenitors within lobuloalveoli during sex hormone exposure or pregnancy. We identify cell migration as a key molecular event that is activated in mesenchymal progenitors in response to epithelium-derived chemoattractant. These findings demonstrate a stromal reservoir of epithelial progenitors and provide insight into cell origins and plasticity during mammary tissue growth.

Brown adipose tissue is a metabolically beneficial organ capable of dissipating chemical energy into heat, thereby increasing energy expenditure. Here, we identify Dot1L, the only known H3K79 methyltransferase, as an interacting partner of Zc3h10 that transcriptionally activates the UCP1 promoter and other BAT genes. Through a direct interaction, Dot1L is recruited by Zc3h10 to the promoter regions of thermogenic genes to function as a coactivator by methylating H3K79. We also show that Dot1L is induced during brown fat cell differentiation and by cold exposure and that Dot1L and its H3K79 methyltransferase activity is required for thermogenic gene program. Furthermore, we demonstrate that Dot1L ablation in mice using UCP1-Cre prevents activation of UCP1 and other target genes to reduce thermogenic capacity and energy expenditure, promoting adiposity. Hence, Dot1L plays a critical role in the thermogenic program and may present as a future target for obesity therapeutics.

Brown adipose tissue (BAT) is a metabolically beneficial organ capable of burning fat by dissipating chemical energy into heat, thereby increasing energy expenditure. Moreover, subcutaneous white adipose tissue can undergo so-called browning/beiging. The recent recognition of the presence of brown or beige adipocytes in human adults has attracted much attention to elucidate the molecular mechanism underlying the thermogenic adipose program. Many key transcriptional regulators critical for the thermogenic gene program centering on activating the UCP1 promoter, have been discovered. Thermogenic gene expression in brown adipocytes rely on co-ordinated actions of a multitude of transcription factors, including EBF2, PPARγ, Zfp516 and Zc3h10. These transcription factors probably integrate into a cohesive network for BAT gene program. Moreover, these transcription factors recruit epigenetic factors, such as LSD1 and MLL3/4, for specific histone signatures to establish the favorable chromatin landscape. In this review, we discuss advances made in understanding the molecular mechanism underlying the thermogenic gene program, particularly epigenetic regulation.

White adipose tissue (WAT) is the primary energy storage organ and its excess contributes to obesity, while brown adipose tissue (BAT) and inducible thermogenic (beige/brite) adipocytes in WAT dissipate energy via UCP1 to maintain body temperature. Adipose tissues can develop during embryogenesis and after birth depending on anatomical origin. In adipose tissue, differentiation of adipose precursors to adipocytes is governed by transcription factors such as PPARγ, C/EBPβ, Zfp423, and Sox9 and this process is tightly regulated by secreted factors including Pref-1 and Wnt. Additionally, thermogenic gene activation in brown and beige adipocytes relies on common transcriptional machinery that includes PRDM16, Zfp516, Zc3h10, and LSD1, play an important role in regulating the thermogenic gene program. These transcription factors actions are also regulated by metabolites that acts as agonists or cofactor. With the presence of BAT-like tissues in human adults, increasing thermogenic activity these tissues may help to combat obesity.

SUMMARY Adipocytes arise from the commitment and differentiation of adipose precursors in white adipose tissue (WAT). In studying adipogenesis, precursor markers, including Pref-1 and PDGFRα, are used to isolate precursors from stromal vascular fractions of WAT, but the relation among the markers is not known. Here, we used the Pref-1 promoter-rtTA system in mice for labeling Pref-1+ cells and for inducible inactivation of the Pref-1 target Sox9. We show the requirement of Sox9 for the maintenance of Pref-1+ proliferative, early precursors. Upon Sox9 inactivation, these Pref-1+ cells become PDGFRα+ cells that express early adipogenic markers. Thus, we show that Pref-1+ cells precede PDGFRα+ cells in the adipogenic pathway and that Sox9 inactivation is required for WAT growth and expansion. Furthermore, we show that in maintaining early adipose precursors, Sox9 activates Meis1, which prevents adipogenic differentiation. Our study also demonstrates the Pref-1 promoter-rtTA system for inducible gene inactivation in early adipose precursor populations., In Brief The relationship among Sox9+, Pref-1+, and PDGFRα+ WAT precursors has not been studied. Gulyaeva et al. show that Pref-1+ cells are early adipose precursors and, upon Sox9 inactivation, they become PDGFRα+ cells at a later stage of the adipogenic pathway. In maintaining Pref-1+ adipose precursors, Sox9 activates Meis1, which prevents adipogenic differentiation., Graphical Abstract

Brown adipose tissue (BAT) is highly metabolically active tissue that dissipates energy via UCP1 as heat, and BAT mass is correlated negatively with obesity. The presence of BAT/BAT-like tissue in humans renders BAT as an attractive target against obesity and insulin resistance. Here, we identify Aifm2, a NADH oxidoreductase domain containing flavoprotein, as a lipid droplet (LD)-associated protein highly enriched in BAT. Aifm2 is induced by cold as well as by diet. Upon cold or β-adrenergic stimulation, Aifm2 associates with the outer side of the mitochondrial inner membrane. As a unique BAT-specific first mammalian NDE (external NADH dehydrogenase)-like enzyme, Aifm2 oxidizes NADH to maintain high cytosolic NAD levels in supporting robust glycolysis and to transfer electrons to the electron transport chain (ETC) for fueling thermogenesis. Aifm2 in BAT and subcutaneous white adipose tissue (WAT) promotes oxygen consumption, uncoupled respiration, and heat production during cold- and diet-induced thermogenesis. Aifm2, thus, can ameliorate diet-induced obesity and insulin resistance.

Fatty acid and triglyceride synthesis increases greatly in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of various enzymes in lipogenic pathway, including fatty acid synthase and glycerol-3-phosphate acyltransferase. Here, we show that JMJD1C is a specific histone demethylase for lipogenic gene transcription in liver. In response to feeding/insulin, JMJD1C is phosphorylated at T505 by mTOR complex to allow direct interaction with USF-1 for recruitment to lipogenic promoter regions. Thus, by demethylating H3K9me2, JMJD1C alters chromatin accessibility to allow transcription. Consequently, JMJD1C promotes lipogenesis in vivo to increase hepatic and plasma triglyceride levels, showing its role in metabolic adaption for activation of the lipogenic program in response to feeding/insulin, and its contribution to development of hepatosteatosis resulting in insulin resistance., In response to insulin, liver cells increase de novo lipogenesis via the transcription factors USF-1 and SREBP. Here the authors show that USF-1 recruits JMJD1C, after its phosphorylation by mTOR, to lipogenic promoters where JMJD1C demethylates histone H3, contributing to lipogenesis by an epigenetic mechanism.

The mammary gland experiences substantial remodeling and regeneration during development and reproductive life, facilitated by stem cells and progenitors that act in concert with physiological stimuli. While studies have focused on deciphering regenerative cells within the parenchymal epithelium, cell lineages in the stroma that may directly contribute to epithelial biology is unknown. Here we identify, in mouse, the transition of a PDGFRα+ mesenchymal cell population into mammary epithelial progenitors. In addition to being adipocyte progenitors, PDGFRα+ cells make a de novo contribution to luminal and basal epithelia during mammary morphogenesis. In the adult, this mesenchymal lineage primarily generates luminal progenitors within lobuloalveoli during sex hormone exposure or pregnancy. We identify cell migration as a key molecular event that is activated in mesenchymal progenitors in response to epithelium-derived chemoattractant. These findings demonstrate a stromal reservoir of epithelial progenitors and provide insight into cell origins and plasticity during mammary tissue growth., The origin and source of mammary gland progenitors and how they interact with the adipose‐rich stroma is unclear. Here, the authors identify PDGFRα+ adipocyte progenitors in the murine mammary stroma as a mesenchymal cell lineage recruited into the expanding epithelium during development, hormone exposure and pregnancy.

Adipose tissue mass and adiposity change throughout the lifespan. During aging, while visceral adipose tissue (VAT) tends to increase, peripheral subcutaneous adipose tissue (SAT) decreases significantly. Unlike VAT, which is linked to metabolic diseases, including type 2 diabetes, SAT has beneficial effects. However, the molecular details behind the aging-associated loss of SAT remain unclear. Here, by comparing scRNA-seq of total stromal vascular cells of SAT from young and aging mice, we identify an Aging-dependent Regulatory Cell (ARC) population that emerges only in SAT of aged mice and humans. ARC express adipose progenitor markers but lacks adipogenic capacity; they secrete high levels of pro-inflammatory chemokines, including Ccl6, to inhibit proliferation and differentiation of neighboring adipose precursors. We also found Pu.1 to be a driving factor for ARC development. We identify an ARC population and its capacity to inhibit differentiation of neighboring adipose precursors, correlating with aging-associated loss of SAT.

SummaryZfp516, a brown fat (BAT)-enriched and cold-inducible transcription factor, promotes transcription of UCP1 and other BAT-enriched genes for non-shivering thermogenesis. Here, we identify lysine-specific demethylase 1 (LSD1) as a direct binding partner of Zfp516. We show that, through interaction with Zfp516, LSD1 is recruited to UCP1 and other BAT-enriched genes, such as PGC1α, to function as a coactivator by demethylating H3K9. We also show that LSD1 is induced during brown adipogenesis and that LSD1 and its demethylase activity is required for the BAT program. Furthermore, we show that LSD1 ablation in mice using Myf5-Cre alters embryonic BAT development. Moreover, BAT-specific deletion of LSD1 via the use of UCP1-Cre impairs the BAT program and BAT development, making BAT resemble WAT, reducing thermogenic activity and promoting obesity. Finally, we demonstrate an in vivo requirement of the Zfp516-LSD1 interaction for LSD1 function in BAT gene activation.

White adipose tissue (WAT) is the primary energy storage organ and its excess contributes to obesity, while brown adipose tissue (BAT) and inducible thermogenic (beige/brite) adipocytes in WAT dissipate energy via Ucp1 to maintain body temperature. BAT and subcutaneous WAT develop perinatally while visceral WAT forms after birth from precursors expressing distinct markers, such as Myf5, Pref-1, Wt1, and Prx1, depending on the anatomical location. In addition to the embryonic adipose precursors, a pool of endothelial cells or mural cells expressing Pparγ, Pdgfrβ, Sma and Zfp423 may become adipocytes during WAT expansion in adults. Several markers, such as Cd29, Cd34, Sca1, Cd24, Pdgfrα and Pref-1 are detected in adult WAT SVF cells that can be differentiated into adipocytes. However, potential heterogeneity and differences in developmental stage of these cells are not clear. Beige cells form in a depot- and condition-specific manner by de novo differentiation of precursors or by transdifferentiation. Thermogenic gene activation in brown and beige adipocytes relies on common transcriptional machinery that includes Prdm16, Zfp516, Pgc1α and Ebf2. Moreover, through changing the chromatin landscape, histone methyltransferases, such as Mll3/4 and Ehmt1, as well as demethylases, such as Lsd1, play an important role in regulating the thermogenic gene program. With the presence of BAT and beige/brite cells in human adults, increasing thermogenic activity of BAT and BAT-like tissues may help promote energy expenditure to combat obesity.

Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT-mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.

Preadipocyte factor-1 (Pref-1) is made as a transmembrane protein containing EGF-repeats at the extracellular domain that can be cleaved to generate a biologically active soluble form. Pref-1 is found in islet β-cells and its level has been reported to increase in neonatal rat islets upon growth hormone treatment. We found here that Pref-1 can promote growth of pancreatic tumor derived AR42J cells. To examine Pref-1 function in pancreatic islets invivo, we generated transgenic mouse lines overexpressing the Pref-1/hFc in islet β-cells using rat insulin II promoter (RIP). These transgenic mice exhibit an increase in islet mass with higher proportion of larger islets in pancreas compared to wild-type littermates. This is in contrast to pancreas from Pref-1 null mice that show higher proportion of smaller islets. Insulin expression and insulin secretion from pancreatic islets from RIP-Pref-1/hFc transgenic mice are increased also. Thus, RIP-Pref-1/hFc transgenic mice show normal glucose levels but with higher plasma insulin levels in both fasting and fed conditions. These mice show improved glucose tolerance. Taken together, we conclude Pref-1 as a positive regulator of islet β-cells and insulin production.

De novo lipogenesis is precisely regulated by nutritional and hormonal conditions. The genes encoding various enzymes involved in this process, such as fatty acid synthase (FASN), are transcriptionally activated in response to insulin. We showed that USF1, a key transcription factor for FASN activation, directly interacted with the Mediator subunit MED17 at the FASN promoter. This interaction recruited Mediator, which can bring POL II and other general transcription machinery to the complex. Moreover, we showed that MED17 was phosphorylated at Ser 53 by casein kinase 2 (CK2) in the livers of fed mice or insulin-stimulated hepatocytes, but not in the livers of fasted mice or untreated hepatocytes. Furthermore, activation of the FASN promoter in response to insulin required this CK2-mediated phosphorylation event, which occurred only in the absence of p38 MAPK–mediated phosphorylation at Thr 570 . Overexpression of a nonphosphorylatable S53A MED17 mutant or knockdown of MED17, as well as CK2 knockdown or inhibition, impaired hepatic de novo fatty acid synthesis and decreased triglyceride content in mice. These results demonstrate that CK2-mediated phosphorylation of Ser 53 in MED17 is required for the transcriptional activation of lipogenic genes in response to insulin.

SummaryPref-1 is an EGF-repeat-containing protein that inhibits adipocyte differentiation. To better understand the origin and development of white adipose tissue (WAT), we generated transgenic mouse models for transient or permanent fluorescent labeling of cells using the Pref-1 promoter, facilitating inducible ablation. We show that Pref-1-marked cells retain proliferative capacity and are very early adipose precursors, prior to expression of Zfp423 or PPARγ. In addition, the Pref-1-marked cells establish that adipose precursors are mesenchymal, but not endothelial or pericytal, in origin. During embryogenesis, Pref-1-marked cells first appear in the dorsal mesenteric region as early as embryonic day 10.5 (E10.5). These cells become lipid-laden adipocytes at E17.5 in the subcutaneous region, whereas visceral WAT develops after birth. Finally, ablation of Pref-1-marked cells prevents not only embryonic WAT development but also later adult adipose expansion upon high-fat feeding, demonstrating the requirement of Pref-1 cells for adipogenesis.

Summary Excessive caloric intake leading to obesity is associated with insulin resistance and dysfunction of islet β cells. High-fat feeding decreases desnutrin (also called ATGL/PNPLA2) levels in islets. Here we show that desnutrin ablation via RIP-Cre (βKO) or RIP-CreER results in hyperglycemia with impaired glucose-stimulated insulin secretion (GSIS). Due to decreased lipolysis, islets have higher TAG content but lower free FA levels. βKO islets exhibit impaired mitochondrial respiration and lower production of ATP required for GSIS, along with decreased expression of PPARδ target genes involved in mitochondrial oxidation. Furthermore, synthetic PPARδ, but not PPARα, agonist restores GSIS and expression of mitochondrial oxidative genes in βKO mice, revealing that desnutrin-catalyzed lipolysis generates PPARδ ligands. Finally, adenoviral expression of desnutrin in βKO islets restores all defects of βKO islet phenotype and function, including GSIS and mitochondrial defects, demonstrating the critical role of the desnutrin-PPARδ-mitochondrial oxidation axis in regulating islet β cell GSIS.

are tightly and coordinately regulated, including enzymes in FA synthesis, such as ACL, ACC, FAS and stearoyl-CoA desaturase, enzymes in the production of NADPH required for FAS activity, such as malic enzyme and glucose-6-phosphate dehydrogenase, as well as enzymes in esterification for TAG synthesis, such as mGPAT and diacylglycerol acyltransferase. Some glycolytic enzymes, such as glucokinase and liver pyruvate kinase, are also regulated in a similar fashion to lipogenic enzymes to provide the carbon source for FA and TAG synthesis. The principal mode of long-term coordinated regulation of lipogenic gene expression in the liver is at the transcriptional level. The expression of the various enzymes mentioned above is very low in the fasted state, correlating with an increase in circulating glucagon, which raises cAMP levels in the liver to activate PKA for suppression of lipogenic gene transcription [2]. By contrast, in the fed state, especially after a high carbohydrate meal, both high blood glucose and insulin levels contribute to the drastic transcriptional activation of lipogenic genes. ChREBP, an E-box binding bHLH/LZ transcription factor that heterodimerizes with Mlx binds to the carbohydrateresponse element (ChoRE) present in lipogenic genes and confers glucose-mediated activation in the liver [3]. ChREBP is phosphorylated by PKA to decrease its nuclear localization, preventing glucose-induced transcriptional activation, whereas dephosphorylation of ChREBP by PP2A leads to activation [4]. Xylulose-5-phosphate produced in the pentose phosphate shunt has been proposed to signal the glucose effect [5]. However, a recent report suggests that glucose-6-phosphate Nonalcoholic fatty liver disease & lipogenesis Nonalcoholic fatty liver disease is the most common chronic liver disease encompassing a range from simple fatty liver (hepatosteatosis) to nonalcoholic steatohepatitis, which can further progress into fibrosis and cirrhosis. Nonalcoholic fatty liver disease is intimately associated with the metabolic syndrome and Type 2 diabetes and may, in effect, be a hepatic manifestation of the metabolic syndrome. Conversely, obesity, dyslipidemia and insulin resistance may also contribute to the development of nonalcoholic fatty liver disease. Hepatosteatosis, or excess accumulation of triglycerides (TAGs) in the liver, may arise due to an impairment of the normal processes of fatty acid (FA) and TAG metabolism (i.e., by increased synthesis of FAs and TAGs, or by decreased hydrolysis of TAG [lipolysis]) and FA oxidation in the liver. Decreased secretion of TAGs into circulation in the form of VLDL can also affect hepatic TAG levels. TAGs in the liver are formed by esterification of glycerol-3-phosphate with FAs. The FAs used for TAG synthesis can be those taken up from lipoproteins or free FAs released from adipose tissue in the circulation, as well as FAs synthesized de novo in the liver from excess dietary carbohydrates. In this article, we focus on the contribution of FA and TAG synthesis to the development of hepatosteatosis.

Fatty acid and triglyceride synthesis is induced in response to feeding and insulin. This lipogenic induction involves coordinate transcriptional activation of lipogenic enzymes, including fatty acid synthase and glycerol-3-phosphate acyltransferase. We recently reported the importance of USF-1 phosphorylation and subsequent acetylation in insulin-induced lipogenic gene activation. Here, we show that Brg1/Brm-associated factor (BAF) 60c is a specific chromatin remodeling component for lipogenic gene transcription in liver. In response to insulin, BAF60c is phosphorylated at S247 by atypical PKCζ/λ, which causes translocation of BAF60c to the nucleus and allows a direct interaction of BAF60c with USF-1 that is phosphorylated by DNA-PK and acetylated by P/CAF. Thus, BAF60c is recruited to form the lipoBAF complex to remodel chromatin structure and to activate lipogenic genes. Consequently, BAF60c promotes lipogenesis in vivo and increases triglyceride levels, demonstrating its role in metabolic adaption to activate the lipogenic program in response to feeding and insulin.

A main function of white adipose tissue is to release fatty acids from stored triacylglycerol for other tissues to use as an energy source. Whereas endocrine regulation of lipolysis has been extensively studied, autocrine and paracrine regulation is not well understood. Here we describe the role of the newly identified major adipocyte phospholipase A(2), AdPLA (encoded by Pla2g16, also called HREV107), in the regulation of lipolysis and adiposity. AdPLA-null mice have a markedly higher rate of lipolysis owing to increased cyclic AMP levels arising from the marked reduction in the amount of adipose prostaglandin E(2) that binds the Galpha(i)-coupled receptor, EP3. AdPLA-null mice have markedly reduced adipose tissue mass and triglyceride content but normal adipogenesis. They also have higher energy expenditure with increased fatty acid oxidation within adipocytes. AdPLA-deficient ob/ob mice remain hyperphagic but lean, with increased energy expenditure, yet have ectopic triglyceride storage and insulin resistance. AdPLA is a major regulator of adipocyte lipolysis and is crucial for the development of obesity.

The preadipocyte factor 1 (Pref-1) is involved in the proliferation and differentiation of various precursor cells. However, the intracellular signaling pathways that control these processes and the role of Pref-1 in the pancreas remain poorly understood. Here, we showed that Pref-1 induces insulin synthesis and secretion via two independent pathways. The overexpression of Pref-1 activated MAPK signaling, which induced nucleocytoplasmic translocation of FOXO1 and PDX1 and led to the differentiation of human pancreatic ductal cells into β-like cells and an increase in insulin synthesis. Concurrently, Pref-1 activated Akt signaling and facilitated insulin secretion. A proteomics analysis identified the Rab43 GTPase-activating protein as a downstream target of Akt. A serial activation of both proteins induced various granular protein syntheses which led to enhanced glucose-stimulated insulin secretion. In a pancreatectomised diabetic animal model, exogenous Pref-1 improved glucose homeostasis by accelerating pancreatic ductal and β-cell regeneration after injury. These data establish a novel role for Pref-1, opening the possibility of applying this molecule to the treatment of diabetes.

Pref-1 (pre-adipocyte factor-1) is known to play a central role in regulating white adipocyte differentiation, but the role of Pref-1 in BAT (brown adipose tissue) has not been analysed. In the present study we found that Pref-1 expression is high in fetal BAT and declines progressively after birth. However, Pref-1-null mice showed unaltered fetal development of BAT, but exhibited signs of over-activation of BAT thermogenesis in the post-natal period. In C/EBP (CCAAT/enhancer-binding protein) α-null mice, a rodent model of impaired fetal BAT differentiation, Pref-1 was dramatically overexpressed, in association with reduced expression of the Ucp1 (uncoupling protein 1) gene, a BAT-specific marker of thermogenic differentiation. In brown adipocyte cell culture models, Pref-1 was mostly expressed in pre-adipocytes and declined with brown adipocyte differentiation. The transcription factor C/EBPδ activated the Pref-1 gene transcription in brown adipocytes, through binding to the proximal promoter region. Accordingly, siRNA (small interfering RNA)-induced C/EBPδ knockdown led to reduced Pref-1 gene expression. This effect is consistent with the observed overexpression of C/EBPδ in C/EBPα-null BAT and high expression of C/EBPδ in brown pre-adipocytes. Dexamethasone treatment of brown pre-adipocytes suppressed Pref-1 down-regulation occurring throughout the brown adipocyte differentiation process, increased the expression of C/EBPδ and strongly impaired expression of the thermogenic markers UCP1 and PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-α]. However, it did not alter normal fat accumulation or expression of non-BAT-specific genes. Collectively, these results specifically implicate Pref-1 in controlling the thermogenic gene expression program in BAT, and identify C/EBPδ as a novel transcriptional regulator of Pref-1 gene expression that may be related to the specific role of glucocorticoids in BAT differentiation.

Obesity has become an epidemic and its prevalence is increasing exponentially. A great deal of focus has been given to understanding the molecular processes that regulate obesity. The characterization of phospholipase A(2)s, especially adipose-specific PLA(2), have lead to a proposed role of their downstream products in the progression of obesity and obesity related disorders. This review summarizes recent developments in the role of PLA(2) and their downstream effects in the development of metabolic disorders.

Pref-1/Dlk1 is made as an epidermal growth factor (EGF) repeat-containing transmembrane protein but is cleaved by tumor necrosis factor alpha converting enzyme (TACE) to generate a biologically active soluble form. Soluble Pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and the subsequent upregulation of Sox9 expression. However, others have implicated Notch in Pref-1 signaling and function. Here, we show that Pref-1 does not interact with, or require, Notch for its function. Instead, we show a direct interaction of Pref-1 and fibronectin via the Pref-1 juxtamembrane domain and fibronectin C-terminal domain. We also show that fibronectin is required for the Pref-1-mediated inhibition of adipocyte differentiation, the activation of ERK/MAPK, and the upregulation of Sox9. Furthermore, disrupting fibronectin binding to integrin by the addition of RGD peptides or by the knockdown of alpha 5 integrin prevents the Pref-1 inhibition of adipocyte differentiation. Pref-1 activates the integrin downstream signaling molecules, FAK and Rac, and ERK activation by Pref-1 is blunted by the knockdown of Rac or by the forced expression of dominant-negative Rac. We conclude that, by interacting with fibronectin, Pref-1 activates integrin downstream signaling to activate MEK/ERK and to inhibit adipocyte differentiation.

Preadipocyte factor 1 (Pref-1) is an EGF-repeat-containing transmembrane protein that inhibits adipogenesis. The extracellular domain of Pref-1 is cleaved by TNF-α converting enzyme to generate the biologically active soluble form of Pref-1. The role of Pref-1 in adipogenesis has been firmly established by in vitro and in vivo studies. Pref-1 activates ERK/MAPK and upregulates Sox9 expression to inhibit adipocyte differentiation. Sox9 directly binds to the promoter regions of CCAAT/enhancer-binding protein-β and CCAAT/enhancer-binding protein-δ in order to suppress their promoter activities in preventing adipocyte differentiation. Here, we describe the function of Pref-1 in adipocyte differentiation and the recent findings on the mechanisms by which Pref-1 inhibits adipocyte differentiation.