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Vani P Sanon, Yehuda Handelsman, Son V Pham, Robert Chilton
IN BRIEF Congenital lipodystrophy is a rare genetic disorder characterized by a near-complete absence of fat cells, hypoleptinemia leading to a voracious appetite, and marked insulin resistance. This article focuses on the known cardiovascular manifestations of patients with congenital lipodystrophy, including cardiomyopathy, cardiac arrhythmias, and accelerated atherosclerosis arising from a markedly deranged metabolic milieu. Future research that targets leptin deficiency (metreleptin) and apoC3 mRNA (antisense oligonucleotide) could open a window for potential pharmacological treatment of this challenging disorder...
October 2016: Clinical Diabetes: a Publication of the American Diabetes Association
Rebecca J Brown, David Araujo-Vilar, Pik To Cheung, David Dunger, Abhimanyu Garg, Michelle Jack, Lucy Mungai, Elif A Oral, Nivedita Patni, Kristina Rother, Julia von Schnurbein, Ekaterina Sorkina, Takara Stanley, Corinne Vigouroux, Martin Wabitsch, Rachel Williams, Tohru Yorifuji
OBJECTIVE: Lipodystrophy syndromes are extremely rare disorders of deficient body fat associated with potentially serious metabolic complications, including diabetes, hypertriglyceridemia, and steatohepatitis. Due to their rarity, most clinicians are not familiar with their diagnosis and management. This practice guideline summarizes diagnosis and management of lipodystrophy syndromes not associated with HIV or injectable drugs. PARTICIPANTS: Seventeen participants were nominated by worldwide endocrine societies or selected by the committee as content experts...
October 6, 2016: Journal of Clinical Endocrinology and Metabolism
Nevin Ajluni, Moahad Dar, John Xu, Adam H Neidert, Elif A Oral
OBJECTIVE: Patients with lipodystrophy have severe metabolic abnormalities (insulin resistance, diabetes, and hypertriglyceridemia) that may increase morbidity and mortality. Metreleptin is approved by the United States Food and Drug Administration for treatment of generalized forms of lipodystrophy. We aimed to determine the efficacy and safety of metreleptin among patients with partial lipodystrophy using an expanded-access model. METHODS: Study FHA101 (ClinicalTrials...
March 2016: Journal of Diabetes & Metabolism
Konstanze Miehle, Thomas Ebert, Susan Kralisch, Annett Hoffmann, Jürgen Kratzsch, Haiko Schlögl, Michael Stumvoll, Mathias Fasshauer
AIMS: Lipodystrophies (LD) are genetic or acquired disorders sharing the symptom of partial or complete adipose tissue deficiency and a dysregulation of adipokines including leptin and adiponectin. Progranulin, an adipokine with proinflammatory and insulin resistance-inducing characteristics, has not been investigated in LD so far. METHODS: Circulating progranulin was determined in LD patients (N=37) and in age-, gender-, and body mass index-matched healthy control subjects (N=37)...
October 2016: Diabetes Research and Clinical Practice
Haiko Schlögl, Karsten Müller, Annette Horstmann, Konstanze Miehle, Janett Püschel, Arno Villringer, Burkhard Pleger, Michael Stumvoll, Mathias Fasshauer
Lipodystrophy (LD) is a rare disease with a paucity of subcutaneous adipocytes and leptin deficiency. Patients often develop severe diabetes and, additionally, show a disturbed eating behavior with reduced satiety. The disturbed eating behavior can be restored by substitution with the leptin analog metreleptin. Long-term effects of metreleptin on resting state brain connectivity in treatment-naive patients with LD have not been assessed. In this study, resting state functional MRI scans and extensive behavioral testing assessing changes in hunger/satiety regulation were performed during the first 52 weeks of metreleptin treatment in nine patients with LD...
August 2016: Diabetes
A Gavrieli, G Panagiotou, C S Mantzoros
Leptin is an adipokine causing browning of adipose tissue, and it thus increases energy expenditure. The same is true for irisin. We studied whether exogenously administered metreleptin affects serum irisin concentrations in humans, which would suggest a direct interplay between leptin and irisin. We performed two studies: a dose-escalating 1-day-long study and a randomized placebo-controlled study. Study 1: 15 healthy, normal-weight and/or obese male and female individuals participated in three 1-day-long trials of metreleptin administration in the fed state...
September 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Konstanze Miehle, Thomas Ebert, Susan Kralisch, Annett Hoffmann, Jürgen Kratzsch, Haiko Schlögl, Michael Stumvoll, Mathias Fasshauer
OBJECTIVE: Patients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD. MATERIAL AND METHODS: Circulating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index...
July 2016: Cytokine
Gilberto J Paz-Filho
Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus...
2016: Neural Plasticity
Amy E Levenson, Mary E Haas, Ji Miao, Rebecca J Brown, Sarah D de Ferranti, Ranganath Muniyappa, Sudha B Biddinger
Leptin treatment has beneficial effects on plasma lipids in patients with lipodystrophy, but the underlying mechanism is unknown. Proprotein convertase subtilisin/kexin type 9 (PCSK9) decreases low-density lipoprotein (LDL) clearance, promotes hypercholesterolemia, and has recently emerged as a novel therapeutic target. To determine the effect of leptin on PCSK9, we treated male and female ob/ob mice with leptin for 4 days via sc osmotic pumps (∼24 μg/d). Leptin reduced body weight and food intake in all mice, but the effects of leptin on plasma PCSK9 and lipids differed markedly between the sexes...
April 2016: Endocrinology
Zhiying Li, Leah Kelly, Myriam Heiman, Paul Greengard, Jeffrey Michael Friedman
In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin...
December 1, 2015: Cell Metabolism
Konstanze Miehle, Thomas Ebert, Susan Kralisch, Annett Hoffmann, Jürgen Kratzsch, Haiko Schlögl, Michael Stumvoll, Mathias Fasshauer
OBJECTIVE: Lipodystrophy (LD) is characterized by loss of adipose tissue, dysregulation of adipokines and severe metabolic complications. Regulation of the insulin resistance-inducing and proinflammatory adipokine chemerin has not been assessed in LD. Therefore, we determined chemerin serum levels in LD, chemerin mRNA expression in insulin-sensitive tissues of LD mice, as well as the impact of metreleptin treatment on circulating chemerin in LD patients. RESEARCH DESIGN AND METHODS: Serum chemerin, as well as clinical and biochemical parameters of glucose metabolism, lipid metabolism, and inflammation, was measured in 37 LD patients and 37 age-, gender- and body mass index-matched controls...
June 2016: Clinical Endocrinology
Gulcin Akinci, Baris Akinci
Lipodystrophies are a heterogeneous group of disorders characterized by congenital or acquired loss of adipose tissue. Recently, metreleptin, a recombinant human leptin analog, has been approved for the treatment of patients with generalized lipodystrophy. Leptin is an adipokine which has a fundamental role in glucose and lipid homeostasis. Metreleptin treatment has been demonstrated to improve metabolic abnormalities such as hyperglycemia, hypertriglyceridemia, increased hepatic fat content and elevated liver enzymes alanine transaminase and aspartate transaminase in patients with generalized lipodystrophy, and to correct hyperphagia that likely occurs as a result of leptin deficiency...
2015: Recent Patents on Endocrine, Metabolic & Immune Drug Discovery
Cristina Adelia Meehan, Elaine Cochran, Andrea Kassai, Rebecca J Brown, Phillip Gorden
The lipodystrophies represent a class of diseases characterized by leptin deficiency. Leptin deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. Metreleptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreleptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties...
2016: Expert Review of Clinical Pharmacology
Jasmin Lebastchi, Nevin Ajluni, Adam Neidert, Elif A Oral
CONTEXT: Acquired generalized lipodystrophy (AGL) is associated with leptin deficiency as a result of adipose tissue loss and hypertriglyceridemia, insulin resistance, and hepatic steatosis. It may coexist with other autoimmune diseases such as Hashimoto's thyroiditis, rheumatoid arthritis, hemolytic anemia, and chronic active hepatitis. Metreleptin therapy has been shown to improve metabolic abnormalities in lipodystrophy, but the effect on AGL patients with active autoimmune disease is unknown...
November 2015: Journal of Clinical Endocrinology and Metabolism
Brent S Abel, Ranganath Muniyappa, Pamela Stratton, Monica C Skarulis, Phillip Gorden, Rebecca J Brown
BACKGROUND: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. AIM: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy. METHODS: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2)...
2016: Neuroendocrinology
S K Choi, S Park, Y Choi, H-S Moon
Intracellular signaling pathways regulated by leptin have largely been studied in metabolically important organs such as adipose tissue and peripheral blood mononuclear cells, suggesting that leptin plays a key role in pathophysiology of insulin resistance. However, whether synthetic analog of leptin, metreleptin, has similar effects on cardiac myocytes (CM) and uterine smooth muscle cells (USMC) has not yet been studied. Hence, in order to address these questions, we extended previous observations and investigated in vitro signaling study whether metreleptin may activate key signaling pathways...
2015: Cellular and Molecular Biology
Nivedita Patni, Abhimanyu Garg
Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes...
September 2015: Nature Reviews. Endocrinology
Beverly G Tchang, Alpana P Shukla, Louis J Aronne
INTRODUCTION: Metreleptin was recently approved by the Food and Drug Administration for the treatment of generalized lipodystrophy, a condition characterized by leptin deficiency. Its efficacy as hormone replacement therapy suggests broader applications in diseases also characterized by leptin abnormalities, such as familial partial lipodystrophy (FPLD), non-alcoholic fatty liver disease (NAFLD), and common obesity. Metreleptin, in conjunction with other pharmacologic interventions, has the potential to address one of the most widespread epidemics of our time, obesity...
July 2015: Expert Opinion on Biological Therapy
Rebecca J Brown, Jean L Chan, Elaine S Jaffe, Elaine Cochran, Alex M DePaoli, Jean-Francois Gautier, Cecile Goujard, Corinne Vigouroux, Phillip Gorden
Acquired generalized lipodystrophy (AGL) is a rare disease thought to result from autoimmune destruction of adipose tissue. Peripheral T-cell lymphoma (PTCL) has been reported in two AGL patients. We report five additional cases of lymphoma in AGL, and analyze the role of underlying autoimmunity and recombinant human leptin (metreleptin) replacement in lymphoma development. Three patients developed lymphoma during metreleptin treatment (two PTCL and one ALK-positive anaplastic large cell lymphoma), and two developed lymphomas (mycosis fungoides and Burkitt lymphoma) without metreleptin...
2016: Leukemia & Lymphoma
Talia Diker-Cohen, Elaine Cochran, Phillip Gorden, Rebecca J Brown
CONTEXT: Lipodystrophies are extreme forms of metabolic syndrome. Metreleptin was approved in the United States for generalized lipodystrophy (GLD) but not partial lipodystrophy (PLD). OBJECTIVE: The objective of the study was to test metreleptin's efficacy in PLD vs GLD and find predictors for treatment response. DESIGN: This was a prospective, single-arm, open-label study since 2000 with continuous enrollment. Current analysis included metreleptin treatment for 6 months or longer as of January 2014...
May 2015: Journal of Clinical Endocrinology and Metabolism
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