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      Lipid Droplets Accumulate in the Hypothalamus of Mice and Humans with and without Metabolic Diseases

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          Background: In peripheral tissues, the lipid droplet (LD) organelle links lipid metabolism, inflammation, and insulin resistance. Little is known about the brain LDs. Objectives: We hypothesized that hypothalamic LDs would be altered in metabolic diseases. Methods: We used immunofluorescence labeling of the specific LD protein, PLIN2, as the approach to visualize and quantify LDs. Results: LDs were abundant in the hypothalamic third ventricle wall layer with similar heterogeneous distributions between control mice and humans. The LD content was enhanced by high-fat diet (HFD) in both wild-type and in low-density lipoprotein receptor deficient ( Ldlr –/– HFD) mice. Strikingly, we observed a lower LD amount in type 2 diabetes mellitus (T2DM) patients when compared with non-T2DM patients. Conclusions: LDs accumulate in the normal hypothalamus, with similar distributions in human and mouse. Moreover, metabolic diseases differently modify LD content in mouse and human. Our results suggest that hypothalamic LD accumulation is an important target to the study of metabolism.

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          Most cited references 35

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          Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation.

          The energy requirements of the brain are very high, and tight regulatory mechanisms operate to ensure adequate spatial and temporal delivery of energy substrates in register with neuronal activity. Astrocytes-a type of glial cell-have emerged as active players in brain energy delivery, production, utilization, and storage. Our understanding of neuroenergetics is rapidly evolving from a "neurocentric" view to a more integrated picture involving an intense cooperativity between astrocytes and neurons. This review focuses on the cellular aspects of brain energy metabolism, with a particular emphasis on the metabolic interactions between neurons and astrocytes. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis.

            The majority of eukaryotic cells synthesize neutral lipids and package them into cytosolic lipid droplets. In vertebrates, triacylglycerol-rich lipid droplets of adipocytes provide a major energy storage depot for the body, whereas cholesteryl ester-rich droplets of many other cells provide building materials for local membrane synthesis and repair. These lipid droplets are coated with one or more of five members of the perilipin family of proteins: adipophilin, TIP47, OXPAT/MLDP, S3-12, and perilipin. Members of this family share varying levels of sequence similarity, lipid droplet association, and functions in stabilizing lipid droplets. The most highly studied member of the family, perilipin, is the most abundant protein on the surfaces of adipocyte lipid droplets, and the major substrate for cAMP-dependent protein kinase [protein kinase A (PKA)] in lipolytically stimulated adipocytes. Perilipin serves important functions in the regulation of basal and hormonally stimulated lipolysis. Under basal conditions, perilipin restricts the access of cytosolic lipases to lipid droplets and thus promotes triacylglycerol storage. In times of energy deficit, perilipin is phosphorylated by PKA and facilitates maximal lipolysis by hormone-sensitive lipase and adipose triglyceride lipase. A model is discussed whereby perilipin serves as a dynamic scaffold to coordinate the access of enzymes to the lipid droplet in a manner that is responsive to the metabolic status of the adipocyte.
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              Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes.

              The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic beta-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic beta-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.

                Author and article information

                S. Karger AG
                February 2021
                18 May 2020
                : 111
                : 3
                : 263-272
                aLaboratory of Immunopharmacology, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil
                bLaboratory of Endocrinology and Department of Endocrinology and Metabolism, Amsterdam Neuroscience, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, The Netherlands
                cNetherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands
                dInstitute for Diabetes and Regeneration, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
                eDepartment of Nutrition and Movement Sciences, Maastricht University Medical Centre+ and NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
                Author notes
                *Clarissa Menezes Maya-Monteiro, Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Fundation (FIOCRUZ), Av. Brasil 4365, Pavilhão 108, sala 48, Rio de Janeiro 21045-900 (Brazil), clarissa@ioc.fiocruz.br; c.maya@amsterdamumc.nl, , Chun-Xia Yi, Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, location AMC, University of Amsterdam, Meibergdreef 9, NL–1105 AZ, Amsterdam (The Netherlands), c.yi@amsterdamumc.nl
                508735 Neuroendocrinology 2021;111:263–272
                © 2020 The Author(s) Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 1, Pages: 10
                Research Article


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