Obesity: From Cell to Patient | EK17

Feb 1, 2021 ‐ Feb 3, 2021



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Tissue and Immune Cell Profiling of Healthy and Unhealthy, Lean and Obese Primates

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-ruggiero-alistaire

Tissue and Immune Cell Profiling of Healthy and Unhealthy, Lean and Obese Primates Alistaire D. Ruggiero1, Masha Block1, Matthew Davis2, Ravichandra Vemuri1, Darla D. DeStephanis1, Swapan K. Das2, Kylie Kavanagh1,3 1Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC, USA 2Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA 3College of Health and Medicine, University of Tasmania, Hobart, AUS Background: More the 93 million people are obese and over 66 million suffer from metabolic syndrome (MetS) in the United States. However, between 5-40% of obese individuals do not suffer from metabolic abnormalities and over 10% of lean individuals do. As an endocrine organ, adipose tissue maintains energy equilibrium and regulates metabolism. We established that African green vervet monkeys (AGMs) demonstrate naturally occurring obesity and MetS without genetic manipulation or high-fat diet consumption. Here, we investigated differences in subcutaneous (SQ) adipose tissue (AT) transcription and circulating monocyte subtypes in AGMs classified as metabolically healthy lean (MHL), metabolically healthy obese (MHO), metabolically unhealthy lean (MUL), and metabolically unhealthy obese (MUO). Methods: A cohort of 44 age- and sex-matched AGMs were classified as MHL, MHO, MUL and MUO according to MetS criteria adjusted for nonhuman primates (waist circumference >40cm, HbA1c >6, fasting blood glucose >100 mg/dL, systolic blood pressure >135mmHg, diastolic blood pressure >85mmHg, triglycerides >125mg/dL, and HDL cholesterol

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Zfp467 Plays a Key role in the Regulation of Thermogenesis in Adipocyte

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-liu-hanghang

Zfp467 Plays a Key role in the Regulation of Thermogenesis in Adipocyte H. Liu1, PT. Le1, F. Gori2, R. Baron2 3, and CJ. Rosen1 1Maine Medical Center Research Institute, Maine Medical Center, Scarborough, ME 04074, USA 2Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA 02115, USA 3Harvard Medical School, Department of Medicine and Endocrine Unit, Massachusetts General Hospital, Boston, 02115, USA Zinc finger proteins (ZFPs) are one of the largest classes of transcription factors in eukaryotic genomes. A small but increasing number of ZFPs have been associated with adipogenesis. Zinc finger protein 467 (Zfp467) was found to enhance adipogenic differentiation by upregulating Pparg. To further investigate the role of Zfp467 in adipose tissues, we generated Zfp467-/- mice. Zfp467-/- mice (-/-) were significantly smaller than Zfp467+/+ mice (+/+) due to both decreased fat mass and fat free mass (p=0.0002). Adipocyte gene expression markers in inguinal fat pads also showed a significant decrease in Leptin and Fabp4 in -/- compared to +/+ (p

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Investigating control of perivascular adipose tissue differentiation during cardiovascular disease

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-stieber-caitlin

Investigating control of perivascular adipose tissue differentiation during cardiovascular disease Title: Investigating control of perivascular adipose tissue differentiation during cardiovascular disease Authors: Katie Stieber1,2, Joshua Boucher3, and Lucy Liaw1,2 1. University of Maine, Orono, ME 2. Maine Medical Center Research Institute, Scarborough, ME 3. IDEXX, Westbrook, ME Introduction: Obesity and cardiovascular disease are prevalent global health problems that are tightly linked. To understand this interaction, we study perivascular adipose tissue (PVAT), which surrounds most vessels and exerts a paracrine effect on the underlying smooth muscle. We are particularly interested in the control of adipogenesis and adipose expansion. Our lab previously found that suppression of Rab27a in pre-adipocytes leads to decreased lipid accumulation in differentiated adipocytes, indicating that Rab27a has a regulatory role during adipogenesis. The focus of this study is to compare human perivascular and subcutaneous adipose tissue (SubQ) from two groups of surgical patients – one undergoing mitral valve repair (VR) and one undergoing coronary artery bypass grafting (CABG). We plan to evaluate the donor groups by prevalence of obesity and diabetes, and expression of thermogenic adipogenic markers and Rab27a. Hypothesis: We hypothesize that VR donors will have a lower BMI, be less likely to be diabetic, and will have adipose tissue that displays more thermogenic features and decreased Rab27a expression, indicating lower adipose differentiation and expansion. Additionally, we expect PVAT to be more thermogenic and have lower Rab27a expression than SubQ. Methods: Demographic information was recorded from each donor. PVAT was collected from donors undergoing VR or CABG surgeries. The pre-adipocytes were isolated from the tissue and expanded into primary cell populations. The pre-adipocytes were induced to differentiate into adipocytes, and the expression of the novel thermogenic marker GRP75 and Rab27a were assessed by immunoblot. Results: The average BMI was 26.53 for those undergoing VR and 31.70 for CABG surgeries. Of the VR donors, 0 out of 11 had diabetes while 5 out of 16 of CABG patients did. Rab27a expression was decreased in VR donors and PVAT as compared to CABG donors and SubQ tissue. GRP75 levels were equivalent between groups. Conclusions: Given the difference in obesity and diabetes prevalence, as well as Rab27a expression, there are clear physiological differences between VR and CABG donors. These differences support the use VR donors as a non-cardiovascular disease control in comparison to CABG donors, who have severe coronary artery disease. Moving forward, we will continue to examine molecular differences between donors, as well as strive to understand Rab27a’s mechanistic control of adipose differentiation. Acknowledgments: This work was supported by the University of Maine institutional training grant 1T32GM132006-01 from the National Institute of General Medical Sciences (PIs: L. Liaw and C. Henry) and R01 HL141149 (PI: L. Liaw).

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Beyond the brain: α-Synuclein’s role as a key regulator of insulin signaling and adipogenesis

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-figueroa-carolina

“Beyond the brain: α-Synuclein’s role as a key regulator of insulin signaling and adipogenesis” Carolina A. Figueroa and Clifford J. Rosen. Rosen Musculoskeletal Laboratory, Maine Medical Research Institute (MMCRI), Scarborough, Maine, USA, 04074. α-Synuclein is a polypeptide encoded by the Snca gene, highly expressed in neurons, but also found in detectable levels in the skeleton and adipose tissue. Aggregation of α-Synuclein is the principal component of Lewy bodies in the central nervous system of PD (Parkinson’s Disease), LDB (Lewy Body Dementia) and some Alzheimer’s disease patients. PD symptoms include progressive immobilization and a range of -often unnoticed - nonmotor symptoms, including osteopenia, body composition alterations and importantly, insulin resistance. In respect to the latter, a recently published trial in PD patients of a GLP-1 agonist showed improved gait and motor function(reference). Previously we used co-expression analyses to show that Snca regulates skeletal homeostasis, and its deletion reduced estrogen deficiency-induced bone loss as well as weight gain in mice (reference). Moreover, we found that Snca expression increases markedly during terminal differentiation of primary adipocytes. To determineα-Synuclein’s intrinsic role in body composition and as a regulator of insulin signaling and lipid metabolism, we generated both conditionally deleted and overexpressing models of α-Synuclein . AdipoCre;Sncafl/fl mice on a high fat diet (HFD) showed no increase in inguinal adipose accrual, markedly reduced weight gain and increased insulin sensitivity compared to mice on a low fat diet (LFD). In vitro models of loss and overexpression of α-Synuclein showed a dose dependent effect on adipocyte differentiation and insulin signaling. For example, loss of α-Synuclein in vitro revealed a decrease in adipogenesis, and pAKT and, increased levels of AKT, pIRβ and pSHC. Mutated α-Synuclein overexpression (A53Ttg/tg) led to greater adipogenesis and increased levels of IRS1, IRS2 and pAKT/AKT. After insulin treatment of primary adipocytes, α-Synuclein expression increased and the protein relocated to the nucleus in control cells, but not in A53Ttg/tg cells, likely due to aggregation of α-Synuclein complexes. In sum, α-Synuclein regulates adipogenesis in a cell autonomous manner, and modulates insulin responsiveness by affecting the levels of pAKT/AKT, IRS1/2 and insulin receptor β. Future research is essential to understand the local and systemic effects of α-Synuclein signaling in adipose metabolism to shed light on potential treatments for insulin resistance in PD patients.

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Peripheral Effect of Adipogenesis on ATM Expression and Mirna-181b Levels in Cardiomyoblasts

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-botha-danelle

Peripheral Effect of Adipogenesis on ATM Expression and Mirna-181b Levels in Cardiomyoblasts Danélle Botha (a), Marguerite Blignaut (a), Hanél Sadie-van Gijsen (a), Paul van Jaarsveld (b), Barbara Huisamen (a) (a) Centre for Cardio-metabolic Research in Africa (CARMA), Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa. (b) Non-Communicable Diseases Research Unit (NCDRU), South African Medical Research Council (SAMRC). (19198639@sun.ac.za) Obesity is a risk factor for metabolic abnormalities that precede type II diabetes and cardiovascular diseases. Adipose tissue communicates with peripheral organs through endocrine secretions, which become dysregulated during obesity. In turn, dysregulated adipose secretions may influence the protein levels of metabolic sensor proteins, including mammalian target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK), in peripheral tissues. Ataxia-telangiectasia mutated kinase (ATM) regulates glucose and redox homeostasis and is decreased in muscle and cardiac tissues of obese and insulin resistant animals. ATM down-regulation therefore represents a potential link between obesity and cardiac metabolic dysfunction, although the underlying mechanism is unknown. MicroRNAs (miRNAs) regulate protein translation in health and disease and are a potential mechanism for ATM regulation in obesity. Thus, this study investigated the effect of in vitro secretions in conditioned media (CM) from adipose stem cells (ASCs) and their differentiated adipocyte counterparts obtained from the subcutaneous and visceral fat depots of control (n=4) and high-fat diet (HFD, n=4) male Wistar rats on i) ATM, mTORC1 and AMPK levels and activity (Western blot) and ii) levels of miR-181b that targets ATM in silico (qRT-PCR) in H9c2 cardiomyoblasts. The CM fatty acid composition was determined with GC-FID. Adipocytes secreted higher levels of palmitic acid (p

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Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control metabolism, stress responses and healthy aging in C. elegans

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-possik-elite

Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control metabolism, stress responses and healthy aging in C. elegans Authors/Affiliation Elite Possik1,2, Clémence Schmitt1,2, Anfal Al-Mass1,2, Johanne Morin1,2, Heidi Erb1,2, Wahab Kahloan1,2, J Alex Parker3, S.R. Murthy Madiraju1,2, and Marc Prentki1,2 1 Department of Nutrition, Université de Montréal, Montreal Diabetes Research Center, CRCHUM, Montréal, Canada. 2 Department of Biochemistry and Molecular Medicine, Montreal Diabetes Research Center, CRCHUM, Montréal, Canada. 3 Department of Neurosciences, CRCHUM, Montréal, Canada. Corresponding Authors Marc Prentki; marc.prentki@umontreal.ca S.R. Murthy Madiraju: murthy.madiraju@crchum.qc.ca Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we studied the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol 3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate (Gro3P) to glycerol. Gro3P is a key metabolite that regulates flux of various metabolic pathways and particularly, the glycerolipid/fatty acid (GL/FA) cycle associated with obesity, type-2-diabetes, and cardiometabolic disorders. We identify three Pgp homologues in C. elegans (pgph1, pgph-2, and pgph-3) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis and contributes to stress responses and healthy aging. Hyperosmotic and high glucose stresses induce pgph transcripts, glycerol production, and salt stress adaptation in a PGPH-dependent manner. Using targeted metabolomics, we find that Gro3P accumulates in pgph mutant animals in basal conditions and more prominently following salt and glucose stresses, while most intermediary metabolites are rarely altered by PGPH loss. Using an unbiased transcription factors RNAi screen, we further identify transcriptional regulators of pgph-2 and pgph-3 salt-mediated expression. Loss of PGPH increases fat deposition, exacerbates glucotoxicity, decreases resistance to various stresses, shortens median lifespan and decreases healthspan parameters. Importantly, pgph-2 overexpression reduces fat deposition with age at basal and glucose excess conditions without restricting animal feeding or decreasing reproduction. Overexpression of pgph-2 improves healthspan and protects from glucotoxicity retarding age-related locomotor decline in normal and high glucose conditions. Strikingly, our data suggest that the overexpression of pgph-2 partly mimics the beneficial effects of dietary restriction. Overall, the results demonstrate that G3PP/PGP is a novel evolutionary conserved regulator of glucose and fat metabolism that protects against nutrient and environmental stresses and is involved in glucose detoxification and healthy aging.

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Female obese mice have a higher mortality rate and altered immune responses following flavivirus infection in comparison to wild type mice

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-geerling-elizabeth

Female obese mice have a higher mortality rate and altered immune responses following flavivirus infection in comparison to wild type mice Elizabeth Geerling1, Mariah Hassert1, E Taylor Stone1, Tara L. Steffen1 and Amelia K. Pinto1 1Saint Louis University, St. Louis, MO 63104 Department of Molecular Microbiology and Immunology A rise in adiposity in the United States has resulted in more than 70% of adults being overweight or obese (National Center for Health Statistics). Globally, areas that have seen a dramatic rise in obesity have also seen a significant increase in emerging arboviral pathogens. Regions of South and Central America have particularly suffered from this “double disease burden” (World Health Organization). Studies done using influenza, hepatitis C, West Nile and dengue viruses have shown that excessive adiposity increases host susceptibility to viral infection and alters immune responses to vaccination. Similarly, obese individuals have a greater risk for developing COVID-19 following SARS-CoV-2 infection, with longer average hospital stays and a higher mortality rate when compared to non-obese individuals. However, limited research has been done to identify mechanisms responsible for impaired immune function. Based on published studies and our preliminary data, we hypothesized that obesity-associated chronic inflammation alters the immune system, enhancing susceptibility to viral diseases and hindering vaccine efficacy. To study how obesity-associated immune inflammation impacts virus disease severity, we are using West Nile virus and SARS-CoV-2 in murine models of obesity. By infecting regular chow-fed (wt) and high fat diet-induced obese (ob) mice, we compared virus-specific immune responses at different time points post infection. Results from these studies indicate that female ob mice have a higher mortality rate, dysfunctional virus-specific T cell responses and lowered efficacy of neutralizing antibodies. These results demonstrate that obesity can lead to enhanced disease severity following viral infection and may have long term consequences for the generation of protective immune responses to vaccination. We are currently conducting studies to determine if immune cells primed in the obese environment are protective, if chronic inflammation leads to epigenetic changes that alter T cell effector functions, the role of sex steroid hormones in immune response differences between male and female ob mice and differences in immunological responses and protection from lethal challenge between wt and ob mice following vaccination.

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Manipulation of the ghrelin receptor in the olfactory bulb affects smell and metabolism

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-stark-romana

Manipulation of the ghrelin receptor in the olfactory bulb affects smell and metabolism Romana Stark (Monash University), Elizabeth Kleeman (Monash University), Jeffrey Zigman (UT Southwestern), Zane Andrews (Monash University) Olfactory dysfunction contributes to many metabolic and mental illnesses in humans and many animals rely on olfaction for normal exploratory behaviour and food acquisition. Interestingly, changes in metabolic state, such as reduced caloric intake during fasting, enhances olfactory processing in both humans and animals. The mechanism linking metabolic state and olfaction remains unknown. Ghrelin is a hormone that regulates metabolism, mood, and memory at various central nervous system (CNS) locations via its receptor under a state of energy deficit. Although the ghrelin receptors are highly expressed in the olfactory bulb (OB), its function remains unknown. We investigated whether ghrelin receptors in the OB increases olfaction performance in fed and fasted conditions and whether or not this influences mood and metabolic parameters using a number of behavioural and metabolic challenges. We employed a viral genetic knockdown approach to chronically delete ghrelin receptors specifically in the OB in ghrelin receptor floxed mice crossed with cre-depednent tdTomato reporter mice to aid viral spread and knockdown validation. 10 week old adult mice were injected with AAV-cre (AAV5 pmSyn1-EBFP-Cre) in to the OB. Deletion of ghrelin receptors in the OB significantly affected olfactory performance in olfactory discrimination and habituation tasks in both fed and fasted mice, as well as increased the latency to find food under both fasted and ghrelin-induced conditions. A two-bottle choice assay for saccharin vs water indicated that mice lacking ghrelin receptors in the OB were completely anhedonic and did not show a preference for saccharin. In support of this, we observed significantly increased anxiety and reduced exploratory locomotor activity in 3 independent anxiety behavioural tasks. Intriguingly, mice increased body weight, fat mass and high blood glucose, indicating metabolic dysfunction. We conclude that OB GHSR maintains olfactory sensitivity under fasted conditions, leading to a number of behavioural and metabolic adaptations to help a mammal detect and respond appropriately to food and odour cues. These results highlight both a new CNS site of action and novel functions for ghrelin as a CNS signalling molecule. These findings can potentially inform future therapies aimed at treating both olfactory and metabolic diseases.

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Activation of G protein-coupled estrogen receptor can yield negative energy balance in leptin resistant mice model

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-park-sohee

Activation of G protein-coupled estrogen receptor can yield negative energy balance in leptin resistant mice model So Hee Park1, Chul Hoon Kim2, and Obin Kwon1 1Department of Biomedical Science, Seoul National University College of Medicine, Seoul, Korea 2Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea Abstract Estrogen plays an important role in the control of energy homeostasis in the hypothalamus. Recently, our group suggested that G protein-coupled estrogen receptor (GPER) can be the estrogen receptor that mediates the anorexigenic effect of estrogen through the STAT3 pathway in the hypothalamus. In this study, we investigated whether this GPER-mediated anorexigenic effect can overcome the leptin resistance in which most forms of obesity are involved. To verify our hypothesis, we injected G-1 or ICI 182,780 (agonists of GPER) to ovariectomized female ERα knockout mice or male C57BL/6J mice by intracerebroventricular injection. These mice were monitored for body weight gain and food intake for 24 hrs, and their hypothalamic tissues were analyzed by immunohistochemistry. Female ERα knockout mice showed obese phenotype and leptin resistance. Administration of GPER agonists to these mice significantly decreased food intake and body weight gain. Double immunohistochemistry data exhibited that GPER activation increased the number of pSTAT3-immunoreactive pro-opiomelanocortin (POMC) neurons in the arcuate nucleus. These results suggest that GPER-mediated anorexigenic effect in hypothalamus might overcome leptin resistance in ERα-independent manner, which provides a novel basis for future therapeutic interventions of obesity.

Speaker(s):
  • Sohee Park, BS, Seoul National University College of Medicine

Targeting membrane fatty acid composition by monounsaturated fatty acid for obesity-induced cardiomyopathy

Feb 1, 2021 12:00am ‐ Feb 1, 2021 12:00am

Identification: EK17-eposter-yamamoto-tsunehisa

Targeting membrane fatty acid composition by monounsaturated fatty acid for obesity-induced cardiomyopathy Tsunehisa Yamamoto1, Jin Endo1, Ken Shinmura2, Motoaki Sano1, Keiichi Fukuda1 1. Department of Cardiology, Keio University School of Medicine 2. Department of General Medicine, Hyogo College of Medicine Obesity-induced lipotoxicity causes cardiac dysfunction in our modern lifestyle. Previously, we have shown that an increase in cardiomyocyte membrane saturated fatty acid (SFA)/ monounsaturated FA (MUFA) ratio mediates ER stress, which was implicated in the pathogenesis of SFA-induced cardiomyopathy. Furthermore, SFA suppressed Sirt1/stearoyl-CoA desaturase-1 (SCD1, converting enzyme from SFA to MUFA) signaling, which further worsened the membrane SFA/MUFA ratio. However, the effectiveness of targeting membrane fatty acid composition by MUFA remains unclear. In wild-type mice, 16-weeks SFA-rich high lard diet feeding (HLD) caused activation of PPARα signaling and the accumulation of toxic lipid intermediates (diacylglycerol and ceramide) in the heart to the same extent as a MUFA-rich high olive oil diet feeding (HOD). However, only the HLD impaired Sirt1 activity, SCD1 expression, diastolic function, and cardiac remodeling (hypertrophy and fibrosis). Lipidome analysis showed that HLD-induced diastolic dysfunction coincided with an increase in membrane SFA/MUFA ratio and ER stress. 8-weeks HOD after 8-weeks HLD (HLD→HOD switch) showed the same degree of obesity and PPARα activation with 16-weeks HLD. By contrast, HLD-HOD switched heart were less severe Sirt1/SCD1 signaling dysregulation, increased in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy (hypertrophy, fibrosis, and diastolic dysfunction) compared to 16-weeks HLD. Moreover, in cardiomyocyte-specific Sirt1 knockout mice, HLD→HOD switch also showed less severe increase in membrane SFA/MUFA ratio, ER stress, and cardiomyopathy compared to 16-weeks HLD although decreased SCD1 expression was not changed. We demonstrated that MUFA-rich diet counteracted SFA-induced Sirt1/SCD1 signaling dysregulation and prevented SFA-induced increase in membrane SFA/MUFA ratio. Hence, MUFA-rich diet antagonized SFA-induced ER stress and cardiomyopathy even if Sirt1 deactivated heart (e.g., aged heart). Targeting the cardiomyocyte membrane SFA/MUFA ratio by MUFA might have a new therapeutic potential for SFA-induced cardiomyopathy.

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