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UNPAID CAREGIVING HAS BECOME INCREASINGLY COMMON SINCE THE ONSET OF CUTS TO THE CANADIAN HEALTHCARE SYSTEM IN THE LATE 1980S. YET THIS CRITICAL CARE PROVIDED TO FAMILY AND FRIENDS IS INVISIBLE, LACKING THE FINANCIAL, SOCIAL AND PROGRAM SUPPORT TO PREVENT UNPAID CAREGIVERS FROM DEPLETING THEIR OWN HEALTH AND FINANCIAL RESOURCES. [ABSTRACT FROM AUTHOR]

Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve., Competing Interests: Competing interests: J.R.B. is a member of the Scientific Advisory Board of LUCA Science, Inc.; receives research support from LUCA Science and Edgewise Therapeutics; is a consultant for Columbus Instruments, Inc.; has consulted for DeciBio within the past 12 months; receives royalties from Springer Nature Group; is an inventor on technology licensed to Columbus Instruments, Inc. with royalty rights; is an inventor on pending patent applications related to the treatment of metabolic diseases (63/625,555) and allergic diseases (US20210128689A1) and mitochondria transfer (018984/US); and is a co-founder and holds equity in Symbiogenix, Inc. K.K.S. is a co-founder, holds equity in, and serves on the Scientific Advisory Board for YUVA Biosciences. E.B. holds patents on detection of extracellular mitochondria in inflammatory conditions (WO2015051466A1) and on mitochondrial autoantibodies in autoimmune diseases (WO2022/246565A1), and is a principal investigator and scientific advisor to MitrixBio. L.B. receives grant support from Philips Medical Systems, ZOLL Medical Corp, Nihon Kohden, PCORI, BrainCool and United Therapeutics; is on the Scientific Advisory Board for Nihon Kohden, HP and Philips; holds seven issued patents and several pending patent applications involving the use of medical slurries as human coolant devices, the creation of slurries, reperfusion cocktails, and measurement of respiratory quotient; and serves on committees for the American Heart Association, which has a financial interest in the outcome of resuscitation studies being conducted and that sells training materials worldwide on resuscitation techniques. A.C. is a founder of and scientific advisor to Dragon Biomed and a scientific advisor to Luvigix. J.A.E. has collaborated with Minova Therapeutics. Å.B.G. is a consultant for Lexeo Therapeutics. J.D.M. has pending patents for the isolation and use of isolated mitochondria and is a founder and member of the Scientific Advisory Board and Board of Directors for cellvie. M.K. is the chief scientific officer of Cells for Cells, EVast Bio, and Regenero (Chilean consortium for regenerative medicine) with Corporación de Fomento de la Producción support; has received research support from ANID (National Agency for Research and Development) basal FB210024 and Cells for Cells; is an inventor on patents related to mesenchymal stem cells (pending patents WO2014135924A1, WO20170646770A2, WO2017064672A1 and WO2019051623). R.N. receives research support from LUCA Science, Inc. A.J.S. is an employee of MitoWorld. M.A.T. is a co-founder and shareholder for NanoCav, a private start-up company with licences for mitochondria-transfer techniques and applications. A.R.T. is an inventor of a pending patent related to the diagnostic detection of cf-mtDNA (WO 2016/063122 A1). R.T. is a scientific advisor for Cytokinetics, Inc. and GenKardia, Inc. M.W. has a pending patent (US20210085713A1) related to compositions and methods for treating stroke. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system 1,2 . In fact, it remains physically connected to, and can be influenced by, the peripheral immune system 1 . How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding question. Here, in searching for molecular cues that derive from the CNS and enable its direct communication with the immune system, we identified an endogenous repertoire of CNS-derived regulatory self-peptides presented on major histocompatibility complex class II (MHC-II) molecules in the CNS and at its borders. During homeostasis, these regulatory self-peptides were found to be bound to MHC-II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes. However, in neuroinflammatory disease, the presentation of regulatory self-peptides diminished. After boosting the presentation of these regulatory self-peptides, a population of suppressor CD4 + T cells was expanded, controlling CNS autoimmunity in a CTLA-4- and TGFβ-dependent manner. CNS-derived regulatory self-peptides may be the molecular key to ensuring a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity. This sheds light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases., Competing Interests: Competing interests: M.W.K. and J.K. hold provisional patent applications related to findings presented here., (© 2024. The Author(s).)

The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin secretion, often concomitant with hypoadiponectinemia. As an adipose tissue derived hormone, adiponectin is beneficial for insulin secretion and β cell health and differentiation. However, the down-stream pathway of adiponectin in the pancreatic islets has not been studied extensively. Here, along with the overall reduction of endocrine pancreatic function in islets from adiponectin KO mice, we examine PPARα and HNF4α as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of β cell-specific PPARα and HNF4α expression, we developed doxycycline inducible pancreatic β cell-specific PPARα (β-PPARα) and HNF4α (β-HNF4α) overexpression mice. β-PPARα mice exhibited improved protection from lipotoxicity, but elevated β-oxidative damage in the islets, and also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. β-HNF4α mice showed a more severe phenotype when compared to β-PPARα mice, characterized by lower body weight, small islet mass and impaired insulin secretion. RNA-sequencing of the islets of these models highlights overlapping yet unique roles of β-PPARα and β-HNF4α. Given that β-HNF4α potently induces PPARα expression, we define a novel adiponectin-HNF4α-PPARα cascade. We further analyzed downstream genes consistently regulated by this axis. Among them, the islet amyloid polypeptide (IAPP) gene is an important target and accumulates in adiponectin KO mice. We propose a new mechanism of IAPP aggregation in type 2 diabetes through reduced adiponectin action., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Recent studies have demonstrated that extracellular vesicles (EVs) serve powerful and complex functions in metabolic regulation and metabolic-associated disease, although this field of research is still in its infancy. EVs are released into the extracellular space from all cells and carry a wide range of cargo including miRNAs, mRNA, DNA, proteins, and metabolites that have robust signaling effects in receiving cells. EV production is stimulated by all major stress pathways and, as such, has a role in both restoring homeostasis during stress and perpetuating disease. In metabolic regulation, the dominant stress signal is a lack of energy due to either nutrient deficits or damaged mitochondria from nutrient excess. This stress signal is termed "energetic stress," which triggers a robust and evolutionarily conserved response that engages major cellular stress pathways, the ER unfolded protein response, the hypoxia response, the antioxidant response, and autophagy. This article proposes the model that energetic stress is the dominant stimulator of EV release with a focus on metabolically important cells such as hepatocytes, adipocytes, myocytes, and pancreatic β-cells. Furthermore, this article will discuss how the cargo in stress-stimulated EVs regulates metabolism in receiving cells in both beneficial and detrimental ways. © 2023 American Physiological Society. Compr Physiol 13:5051-5068, 2023., (Copyright © 2023 American Physiological Society. All rights reserved.)

Extracellular vesicles (EVs) are small, lipid-bilayer-bound particles released by cells that can contain important bioactive molecules, including lipids, RNAs, and proteins. Once released in the extracellular environment, EVs can act as messengers locally as well as to distant tissues to coordinate tissue homeostasis and systemic responses. There is a growing interest in not only understanding the physiology of EVs as signaling particles but also leveraging them as minimally invasive diagnostic and prognostic biomarkers (e.g., they can be found in biofluids) and drug-delivery vehicles. On October 30-November 2, 2022, researchers in the EV field convened for the Keystone symposium "Exosomes, Microvesicles, and Other Extracellular Vesicles" to discuss developing standardized language and methodology, new data on the basic biology of EVs and potential clinical utility, as well as novel technologies to isolate and characterize EVs., (© 2023 New York Academy of Sciences.)

Extracellular vesicles (EVs) produced by adipocytes and other adipose tissue (AT) cells are present in the space between cells in the tissue and in circulation. These EVs have been shown to robustly signal between cells in the tissue and in distal organs. AT has unique biophysical properties that require an optimized EV isolation protocol that ensures an uncontaminated EV isolate. This protocol can be used to isolate and characterize the total, heterogeneous population of EVs from the AT., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Caveolin-1 (cav1) is an important structural and signaling component of plasma membrane invaginations called caveolae and is abundant in adipocytes. As previously reported, adipocyte-specific ablation of the cav1 gene (ad-cav1 knockout [KO] mouse) does not result in elimination of the protein, as cav1 protein traffics to adipocytes from neighboring endothelial cells. However, this mouse is a functional KO because adipocyte caveolar structures are depleted. Compared with controls, ad-cav1KO mice on a high-fat diet (HFD) display improved whole-body glucose clearance despite complete loss of glucose-stimulated insulin secretion, blunted insulin-stimulated AKT activation in metabolic tissues, and partial lipodystrophy. The cause is increased insulin-independent glucose uptake by white adipose tissue (AT) and reduced hepatic gluconeogenesis. Furthermore, HFD-fed ad-cav1KO mice display significant AT inflammation, fibrosis, mitochondrial dysfunction, and dysregulated lipid metabolism. The glucose clearance phenotype of the ad-cav1KO mice is at least partially mediated by AT small extracellular vesicles (AT-sEVs). Injection of control mice with AT-sEVs from ad-cav1KO mice phenocopies ad-cav1KO characteristics. Interestingly, AT-sEVs from ad-cav1KO mice propagate the phenotype of the AT to the liver. These data indicate that ad-cav1 is essential for healthy adaptation of the AT to overnutrition and prevents aberrant propagation of negative phenotypes to other organs by EVs., (© 2022 by the American Diabetes Association.)

Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress., Competing Interests: Declaration of interests J.R.B. has a pending patent application related to intercellular mitochondria transfer for the treatment of mitochondrial disorders, is a consultant for DeciBio and Flagship Pioneering, and is a scientific advisor to LUCA Science, Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs), exosomes and microvesicles, is a burgeoning field of biological and biomedical research that may change our understanding of cell communication in plants and animals while holding great promise for the diagnosis of disease and the development of therapeutics. However, the challenge remains to develop a general hypothesis about the role of EVs in physiological homeostasis and pathobiology across kingdoms. While they can act systemically, EVs are often seen to operate locally within a microenvironment. This microenvironment is built as a collection of microunits comprised of cells that interact with each other via EV exchange, EV signaling, EV seeding, and EV disposal. We propose that microunits are part of a larger matrix at the tissue level that collectively communicates with the surrounding environment, including other end-organ systems. Herein, we offer a working model that encompasses the various facets of EV function in the context of the cell biology and physiology of multicellular organisms., (©2022 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.)

Functional adipose tissue is essential for homeostatic maintenance of systemic metabolism. As such, adipose tissue dysfunction, like that seen in the obese state, directly contributes to system-wide pathological metabolism, leading to the development of type 2 diabetes and other obesity-associated comorbidities. In addition to the storage function of adipocytes, they also secrete numerous factors that robustly regulate metabolism-related pathways throughout the body. Many of these factors, in addition to other signaling proteins, RNA species and lipids, are found in extracellular vesicles (EVs) released from adipocytes. EVs are vesicles with a lipid bilayer, known to carry signaling proteins and lipids, mRNAs and miRNAs. Because of this diverse cargo, EVs can have robust and pleotropic signaling effects depending on the receiving target cells. We are only now starting to understand how adipocyte EVs can modulate metabolism within adipose tissue and beyond. Here, we highlight the current literature that demonstrates EV-mediated crosstalk between adipocytes and other tissues or distal cells. We become increasingly aware of the importance of these adipocyte-derived EV signals that establish a so far underappreciated endocrine system. Adipocyte EVs offer a new avenue for pharmacological manipulation of metabolism to treat obesity-related disease., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D., (© 2021. The Author(s).)

Iron overload is positively associated with diabetes risk. However, the role of iron in adipose tissue remains incompletely understood. Here, we report that transferrin-receptor-1-mediated iron uptake is differentially required for distinct subtypes of adipocytes. Notably, adipocyte-specific transferrin receptor 1 deficiency substantially protects mice from high-fat-diet-induced metabolic disorders. Mechanistically, low cellular iron levels have a positive impact on the health of the white adipose tissue and can restrict lipid absorption from the intestine through modulation of vesicular transport in enterocytes following high-fat diet feeding. Specific reduction of adipocyte iron by AAV-mediated overexpression of the iron exporter Ferroportin1 in adult mice effectively mimics these protective effects. In summary, our studies highlight an important role of adipocyte iron in the maintenance of systemic metabolism through an adipocyte-enterocyte axis, offering an additional level of control over caloric influx into the system after feeding by regulating intestinal lipid absorption., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Circular RNAs (circRNAs) are a conserved class of RNAs with diverse functions, including serving as messenger RNAs that are translated into peptides. Here we describe circular RNAs generated by human polyomaviruses (HPyVs), some of which encode variants of the previously described alternative large T antigen open reading frame (ALTO) protein. Circular ALTO RNAs (circALTOs) can be detected in virus positive Merkel cell carcinoma (VP-MCC) cell lines and tumor samples. CircALTOs are stable, predominantly located in the cytoplasm, and N6-methyladenosine (m6A) modified. The translation of MCPyV circALTOs into ALTO protein is negatively regulated by MCPyV-generated miRNAs in cultured cells. MCPyV ALTO expression increases transcription from some recombinant promoters in vitro and upregulates the expression of multiple genes previously implicated in MCPyV pathogenesis. MCPyV circALTOs are enriched in exosomes derived from VP-MCC lines and circALTO-transfected 293T cells, and purified exosomes can mediate ALTO expression and transcriptional activation in MCPyV-negative cells. The related trichodysplasia spinulosa polyomavirus (TSPyV) also expresses a circALTO that can be detected in infected tissues and produces ALTO protein in cultured cells. Thus, human polyomavirus circRNAs are expressed in human tumors and infected tissues and express proteins that have the potential to modulate the infectious and tumorigenic properties of these viruses., Competing Interests: The authors have declared that no competing interests exist.

The adipose tissue stroma is a rich source of molecularly distinct stem and progenitor cell populations with diverse functions in metabolic regulation, adipogenesis, and inflammation. The ontology of these populations and the mechanisms that govern their behaviors in response to stimuli, such as overfeeding, however, are unclear. Here, we show that the developmental fates and functional properties of adipose platelet-derived growth factor receptor beta (PDGFRβ)+ progenitor subpopulations are tightly regulated by mitochondrial metabolism. Reducing the mitochondrial β-oxidative capacity of PDGFRβ+ cells via inducible expression of MitoNEET drives a pro-inflammatory phenotype in adipose progenitors and alters lineage commitment. Furthermore, disrupting mitochondrial function in PDGFRβ+ cells rapidly induces alterations in immune cell composition in lean mice and impacts expansion of adipose tissue in diet-induced obesity. The adverse effects on adipose tissue remodeling can be reversed by restoring mitochondrial activity in progenitors, suggesting therapeutic potential for targeting energy metabolism in these cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of β-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and β-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive β-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing β-cell mass during obesity-related insulin resistance., (© 2019 by the American Diabetes Association.)

Dermal adipose tissue (also known as dermal white adipose tissue and herein referred to as dWAT) has been the focus of much discussion in recent years. However, dWAT remains poorly characterized. The fate of the mature dermal adipocytes and the origin of the rapidly reappearing dermal adipocytes at different stages remain unclear. Here, we isolated dermal adipocytes and characterized dermal fat at the cellular and molecular level. Together with dWAT's dynamic responses to external stimuli, we established that dermal adipocytes are a distinct class of white adipocytes with high plasticity. By combining pulse-chase lineage tracing and single-cell RNA sequencing, we observed that mature dermal adipocytes undergo dedifferentiation and redifferentiation under physiological and pathophysiological conditions. Upon various challenges, the dedifferentiated cells proliferate and redifferentiate into adipocytes. In addition, manipulation of dWAT highlighted an important role for mature dermal adipocytes for hair cycling and wound healing. Altogether, these observations unravel a surprising plasticity of dermal adipocytes and provide an explanation for the dynamic changes in dWAT mass that occur under physiological and pathophysiological conditions, and highlight the important contributions of dWAT toward maintaining skin homeostasis.

Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect in adipocyte biology. Here, we report a role for amyloid precursor protein (APP) in compromising WAT mitochondrial function through a high-fat diet (HFD)-induced, unconventional mis-localization to mitochondria that further promotes obesity. In humans and mice, obese conditions significantly induce APP production in WAT and its enrichment in mitochondria. Mechanistically, a HFD-induced dysregulation of signal recognition particle subunit 54c is responsible for the mis-targeting of APP to adipocyte mitochondria. Mis-localized APP blocks the protein import machinery, leading to mitochondrial dysfunction in WAT. Adipocyte-specific and mitochondria-targeted APP overexpressing mice display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT due to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with significant protection from weight gain and systemic metabolic deficiency. Our data highlights an important role of APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction., Competing Interests: Competing interests All the authors declare no competing interests.

The synthesis of lipid and sterol species through de novo lipogenesis (DNL) is regulated by two functionally overlapping but distinct transcription factors: the sterol regulatory element-binding proteins (SREBPs) and carbohydrate response element binding protein (ChREBP). ChREBP is considered to be the dominant regulator of DNL in adipose tissue (AT); however, the SREBPs are highly expressed and robustly regulated in adipocytes, suggesting that the model of AT DNL may be incomplete. Here we describe a new mouse model of inducible, adipocyte-specific overexpression of the insulin-induced gene 1 (Insig1), a negative regulator of SREBP transcriptional activity. Contrary to convention, Insig1 overexpression did block AT lipogenic gene expression. However, this was immediately met with a compensatory mechanism triggered by redox activation of mTORC1 to restore SREBP1 DNL gene expression. Thus, we demonstrate that SREBP1 activity sustains adipocyte lipogenesis, a conclusion that has been elusive due to the constitutive nature of current mouse models.

We have previously reported that the carboxy-terminal proteolytic cleavage product of the COL6α3 chain that we refer to as "endotrophin" has potent effects on transformed mammary ductal epithelial cells in rodents. Endotrophin (ETP) is abundantly expressed in adipose tissue. It is a chemoattractant for macrophages, exerts effects on endothelial cells and through epithelial-mesenchymal transition (EMT) enhances progression of tumor cells. In a recombinant form, human endotrophin exerts similar effects on human macrophages and endothelial cells as its rodent counterpart. It enhances EMT in human breast cancer cells and upon overexpression in tumor cells, the cells become chemoresistant. Here, we report the identification of endotrophin from human plasma. It is circulating at higher levels in breast cancer patients. We have developed neutralizing monoclonal antibodies against human endotrophin and provide evidence for the effectiveness of these antibodies to curb tumor growth and enhance chemosensitivity in a nude mouse model carrying human tumor cell lesions. Combined, the data validate endotrophin as a viable target for anti-tumor therapy for human breast cancer and opens the possibility for further use of these new reagents for anti-fibrotic approaches in liver, kidney, bone marrow and adipose tissue.

We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knockout of caveolin 1 (cav1) protein. Although we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs. AT-derived EVs contain proteins and lipids capable of modulating cellular signaling pathways. Furthermore, this mechanism facilitates transfer of plasma constituents from ECs to the adipocyte. The transfer event is physiologically regulated by fasting/refeeding and obesity, suggesting EVs participate in the tissue response to changes in the systemic nutrient state. This work offers new insights into the complex signaling mechanisms that exist among adipocytes, stromal vascular cells, and, potentially, distal organs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cardiac metabolic inflexibility is driven by robust up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) and phosphorylation-dependent inhibition of pyruvate dehydrogenase (PDH) within a single day of feeding mice a high fat diet. In the current study, we have discovered that PDK4 is a short lived protein (t ½ ∼ 1 h) and is specifically degraded by the mitochondrial protease Lon. Lon does not rapidly degrade PDK1 and -2, indicating specificity toward the PDK isoform that is a potent modulator of metabolic flexibility. Moreover, PDK4 degradation appears regulated by dissociation from the PDH complex dependent on the respiratory state and energetic substrate availability of mouse heart mitochondria. Finally, we demonstrate that pharmacologic inhibition of PDK4 promotes PDK4 degradation in vitro and in vivo These findings reveal a novel strategy to manipulate PDH activity by selectively targeting PDK4 content through dissociation and proteolysis., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)

There are three dominant contributors to the pathogenesis of dysfunctional adipose tissue (AT) in obesity: unresolved inflammation, inappropriate extracellular matrix (ECM) remodeling and insufficient angiogenic potential. The interactions of these processes during AT expansion reflect both a linear progression as well as feed-forward mechanisms. For example, both inflammation and inadequate angiogenic remodeling can drive fibrosis, which can in turn promote migration of immune cells into adipose depots and impede further angiogenesis. Therefore, the relationship between the members of this triad is complex but important for our understanding of the pathogenesis of obesity. Here we untangle some of these intricacies to highlight the contributions of inflammation, angiogenesis, and the ECM to both "healthy" and "unhealthy" AT expansion., Competing Interests: The authors have declared that no conflict of interest exists.

Resistin, and its closely related homologs, the resistin-like molecules (RELMs) have been implicated in metabolic dysregulation, inflammation, and cancer. Specifically, RELMβ, expressed predominantly in the goblet cells in the colon, is released both apically and basolaterally, and is hence found in both the intestinal lumen in the mucosal layer as well as in the circulation. RELMβ has been linked to both the pathogenesis of colon cancer and type 2 diabetes. RELMβ plays a complex role in immune system regulation, and the impact of loss of function of RELMβ on colon cancer and metabolic regulation has not been fully elucidated. We therefore tested whether Retnlβ (mouse ortholog of human RETNLβ) null mice have an enhanced or reduced susceptibility for colon cancer as well as metabolic dysfunction. We found that the lack of RELMβ leads to increased colonic expression of T helper cell type-2 cytokines and IL-17, associated with a reduced ability to maintain intestinal homeostasis. This defect leads to an enhanced susceptibility to the development of inflammation, colorectal cancer, and glucose intolerance. In conclusion, the phenotype of the Retnlβ null mice unravels new aspects of inflammation-mediated diseases and strengthens the notion that a proper intestinal barrier function is essential to sustain a healthy phenotype., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Adipose hyaluronan is increasingly recognized as an active player in adipose tissue fibrosis and metabolic dysfunction. However, this role poses as many challenges as opportunities for therapeutic targeting of adipose tissue dysfunction during nutrient oversupply., (Copyright © 2016, American Association for the Advancement of Science.)

Cardiac function depends on the ability to switch between fatty acid and glucose oxidation for energy production in response to changes in substrate availability and energetic stress. In obese and diabetic individuals, increased reliance on fatty acids and reduced metabolic flexibility are thought to contribute to the development of cardiovascular disease. Mechanisms by which cardiac mitochondria contribute to diet-induced metabolic inflexibility were investigated. Mice were fed a high fat or low fat diet for 1 d, 1 wk, and 20 wk. Cardiac mitochondria isolated from mice fed a high fat diet displayed a diminished ability to utilize the glycolytically derived substrate pyruvate. This response was rapid, occurring within the first day on the diet, and persisted for up to 20 wk. A selective increase in the expression of pyruvate dehydrogenase kinase 4 and inhibition of pyruvate dehydrogenase are responsible for the rapid suppression of pyruvate utilization. An important consequence is that pyruvate dehydrogenase is sensitized to inhibition when mitochondria respire in the presence of fatty acids. Additionally, increased expression of pyruvate dehydrogenase kinase 4 preceded any observed diet-induced reductions in the levels of glucose transporter type 4 and glycolytic enzymes and, as judged by Akt phosphorylation, insulin signaling. Importantly, diminished insulin signaling evident at 1 wk on the high fat diet did not occur in pyruvate dehydrogenase kinase 4 knockout mice. Dietary intervention leads to a rapid decline in pyruvate dehydrogenase kinase 4 levels and recovery of pyruvate dehydrogenase activity indicating an additional form of regulation. Finally, an overnight fast elicits a metabolic response similar to that induced by high dietary fat obscuring diet-induced metabolic changes. Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production.