scholarly journals Lipodystrophies—Disorders of the Fatty Tissue

2020 ◽  
Vol 21 (22) ◽  
pp. 8778
Author(s):  
Birgit Knebel ◽  
Dirk Müller-Wieland ◽  
Jorg Kotzka
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Fat Distribution ◽  
Fat Cells ◽  
Fatty Tissue ◽  
Loss Of Function ◽  
Metabolic Complications ◽  
Crucial Difference

Lipodystrophies are a heterogeneous group of physiological changes characterized by a selective loss of fatty tissue. Here, no fat cells are present, either through lack of differentiation, loss of function or premature apoptosis. As a consequence, lipids can only be stored ectopically in non-adipocytes with the major health consequences as fatty liver and insulin resistance. This is a crucial difference to being slim where the fat cells are present and store lipids if needed. A simple clinical classification of lipodystrophies is based on congenital vs. acquired and generalized vs. partial disturbance of fat distribution. Complications in patients with lipodystrophy depend on the clinical manifestations. For example, in diabetes mellitus microangiopathic complications such as nephropathy, retinopathy and neuropathy may develop. In addition, due to ectopic lipid accumulation in the liver, fatty liver hepatitis may also develop, possibly with cirrhosis. The consequences of extreme hypertriglyceridemia are typically acute pancreatitis or eruptive xanthomas. The combination of severe hyperglycemia with dyslipidemia and signs of insulin resistance can lead to premature atherosclerosis with its associated complications of coronary heart disease, peripheral vascular disease and cerebrovascular changes. Overall, lipodystrophy is rare with an estimated incidence for congenital (<1/1.000.000) and acquired (1–9/100.000) forms. Due to the rarity of the syndrome and the phenotypic range of metabolic complications, only studies with limited patient numbers can be considered. Experimental animal models are therefore useful to understand the molecular mechanisms in lipodystrophy and to identify possible therapeutic approaches.

scholarly journals Biomediators in Polycystic Ovary Syndrome and Cardiovascular Risk

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1350
Author(s):  
Srdan Pandurevic ◽  
Djuro Macut ◽  
Flaminia Fanelli ◽  
Uberto Pagotto ◽  
Alessandra Gambineri
Keyword(s):  
Insulin Resistance ◽  
Polycystic Ovary Syndrome ◽  
Molecular Mechanisms ◽  
Polycystic Ovary ◽  
Clinical Manifestations ◽  
Molecular Heterogeneity ◽  
Ovary Syndrome ◽  
Metabolic Complications ◽  
Early Predictors ◽  
Cv Disease

Polycystic ovary syndrome (PCOS) is extremely heterogeneous in terms of clinical manifestations. The variability of the syndrome’s phenotype is derived from the genetic and molecular heterogeneity, with a great deal of environmental factors that may have long-term health consequences, such as metabolic and cardiovascular (CV) diseases. There is no doubt that women with PCOS suffer from metabolic complications more than their age-matched counterparts in the general population and at an earlier age. Obesity, low steroid hormone-binding globulin (SHBG), hyperandrogenemia, insulin resistance, and compensatory hyperinsulinemia are biomediators and early predictors of metabolic complications in PCOS. Doubts remain about the real risk of CV diseases in PCOS and the molecular mechanisms at the basis of CV complications. Based on that assumption, this review will present the available evidence on the potential implications of some biomediators, in particular, hyperandrogenism, estrogen-progesterone imbalance, insulin resistance, and low SHBG, in the processes leading to CV disease in PCOS, with the final aim to propose a more accurate CV risk assessment.

Inflammation and impaired adipogenesis in hypertrophic obesity in man

2009 ◽  
Vol 297 (5) ◽  
pp. E999-E1003 ◽  
Author(s):  
Birgit Gustafson ◽  
Silvia Gogg ◽  
Shahram Hedjazifar ◽  
Lachmi Jenndahl ◽  
Ann Hammarstedt ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Subcutaneous Adipose Tissue ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Preadipocyte Differentiation ◽  
Metabolic Complications ◽  
Adipose Cell ◽  
Subcutaneous Adipose ◽  
Adipose Cell Size

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.

scholarly journals Towards improved precision and a new classification of diabetes mellitus

2021 ◽  
Author(s):  
Emma Ahlqvist ◽  
Rashmi B Prasad ◽  
Leif Groop
Keyword(s):  
Insulin Resistance ◽  
Personalized Medicine ◽  
Fatty Liver ◽  
Early Stage ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Patient Health ◽  
The Right

Type 2 diabetes (T2D) is one of the fastest increasing diseases worldwide. Although it is defined by a single metabolite, glucose, it is increasingly recognized as a highly heterogeneous disease with varying clinical manifestations. Identification of different subtypes at an early stage of disease when complications might still be prevented could hopefully allow for more personalized medicine. An important step towards precision medicine would be to target the right resources to the right patients, thereby improving patient health and reducing health costs for the society. More well-defined disease populations also offer increased power in experimental, genetic and clinical studies. In a recent study, we used six clinical variables (GAD autoantibodies, age at onset of diabetes, HbA1c, BMI, and simple measures of insulin resistance and insulin secretion (so called HOMA estimates) to cluster adult-onset diabetes patients into five subgroups. These subgroups have been robustly reproduced in several populations worldwide and are associated with different risks of diabetic complications and responses to treatment. Importantly, the group with severe insulin-deficient diabetes (SIDD) had increased risk of retinopathy and neuropathy, whereas the severe insulin-resistant diabetes (SIRD) group has the highest risk for diabetic kidney disease (DKD) and fatty liver. This emphasizes the key role of insulin resistance in the pathogenesis of DKD and fatty liver in T2D. In conclusion, this novel sub-classification, breaking down T2D in clinically meaningful subgroups, provides the prerequisite framework for expanded personalized medicine in diabetes beyond what is already available for monogenic and to some extent type 1 diabetes.

scholarly journals Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver

2021 ◽  
Author(s):  
Sunmi Seok ◽  
Hao Sun ◽  
Young-Chae Kim ◽  
Byron Kemper ◽  
Jongsook Kim Kemper
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Farnesoid X Receptor ◽  
Dependent Manner ◽  
Obese Mice ◽  
Metabolic Complications ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects ◽  
Elevated Expression ◽  
Glucose And Lipid Homeostasis

Aberrantly elevated expression in obesity of microRNAs (miRs), including miR-802, contributes to obesity-associated metabolic complications but the mechanisms underlying the elevated expression are unclear. Farnesoid-X-Receptor (FXR), a key regulator of hepatic energy metabolism, has great potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced Small Heterodimer Partner (SHP) regulates expression of <i>miR-802</i> to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of <i>miR-802 </i>by<i> </i>Aromatic Hydrocarbon Receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In non-alcoholic fatty liver disease patients and obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the <i>miR-802</i> promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of <i>miR-802</i> by FXR-SHP is defective in obesity, resulting in increased <i>miR-802</i> levels, insulin resistance and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.

scholarly journals RIPK1-Associated Inborn Errors of Innate Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahui Zhang ◽  
Taijie Jin ◽  
Ivona Aksentijevich ◽  
Qing Zhou
Keyword(s):  
Immune Deficiency ◽  
Molecular Mechanisms ◽  
Clinical Manifestations ◽  
Physiological Role ◽  
Model Organisms ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Post Translational Modifications ◽  
Cell Death Signaling

RIPK1 (receptor-interacting serine/threonine-protein kinase 1) is a key molecule for mediating apoptosis, necroptosis, and inflammatory pathways downstream of death receptors (DRs) and pattern recognition receptors (PRRs). RIPK1 functions are regulated by multiple post-translational modifications (PTMs), including ubiquitination, phosphorylation, and the caspase-8-mediated cleavage. Dysregulation of these modifications leads to an immune deficiency or a hyperinflammatory disease in humans. Over the last decades, numerous studies on the RIPK1 function in model organisms have provided insights into the molecular mechanisms of RIPK1 role in the maintenance of immune homeostasis. However, the physiological role of RIPK1 in the regulation of cell survival and cell death signaling in humans remained elusive. Recently, RIPK1 loss-of-function (LoF) mutations and cleavage-deficient mutations have been identified in humans. This review discusses the molecular pathogenesis of RIPK1-deficiency and cleavage-resistant RIPK1 induced autoinflammatory (CRIA) disorders and summarizes the clinical manifestations of respective diseases to help with the identification of new patients.

scholarly journals Update on the synergistic effect of HSL and insulin in the treatment of metabolic disorders

2019 ◽  
Vol 10 ◽  
pp. 204201881987730 ◽  
Author(s):  
Yu-Long Lan ◽  
Jia-Cheng Lou ◽  
Wen Lyu ◽  
Bo Zhang
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Energy Demand ◽  
Insulin Injection ◽  
Current Data ◽  
Hormone Sensitive Lipase ◽  
Future Research ◽  
Metabolic Complications ◽  
Mutual Regulation ◽  
Impaired Insulin Action

Hormone-sensitive lipase (HSL) is one of the three lipases in adipose tissue present during periods of energy demand. HSL is tightly controlled by insulin regulation via the central and peripheral systems. The suppressive effects of insulin on HSL are also associated with complex crosstalk with other pathways in the metabolic network. Because impaired insulin action is the driving force behind the pathogenesis of diabetes and other metabolic complications, elucidation of the intricate relationships between HSL and insulin may provide an in-depth understanding of these pandemic diseases and potentially identify strategies to inhibit disease development. Insulin not only differentially regulates HSL isoform transcription but also post-transcriptionally affects HSL phosphorylation by stimulating PKA and endothelin (ET-1), and controls its expression indirectly via regulating the activity of growth hormone (GH). In addition, a rapid elevation of HSL levels was detected after insulin injection in patients, which suggests that the inhibitory effects of insulin on HSL can be overridden by insulin-induced hypoglycemia. Conversely, individuals with hereditary HSL deficiency, and animals with experimental HSL deletion, showed major disruptions in mRNA/protein expression in insulin signaling pathways, ultimately leading to insulin resistance, diabetes, and fatty liver. Notably, HSL inactivation could cause insulin-independent fatty liver, while insulin resistance induced by HSL deficiency may further aggravate disease progression. The common beliefs that HSL is the overall rate-limiting enzyme in lipolysis and that insulin is an inhibitor of HSL have been challenged by recent discoveries; therefore, a renewed examination of their relationships is required. In this review, by analyzing current data related to the role of, and mutual regulation between, HSL and insulin and discussing unanswered questions and disparities in different lines of studies, the authors intend to shed light on our understanding of lipid metabolism and provide a rational basis for future research in drug development.

Sign in / Sign up

Export Citation Format

Share Document