Lipodystrophies-Disorders of the Fatty Tissue Knebel, Birgit; Müller-Wieland, Dirk; Kotzka, Jorg
International journal of molecular sciences,
11/2020, Letnik:
21, Številka:
22
Journal Article
Recenzirano
Odprti dostop
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.
Aims/hypothesis
Emerging evidence suggests that in addition to hyperglycaemia, dyslipidaemia could represent a contributing pathogenetic factor to diabetic neuropathy, while obesity and insulin ...resistance play a role in the development of diabetic cardiac autonomic neuropathy (CAN) characterised by reduced heart rate variability (HRV), particularly in type 2 diabetes. We hypothesised that distinct lipid metabolites are associated with diminished HRV in recent-onset type 2 diabetes rather than type 1 diabetes.
Methods
We analysed 127 plasma lipid metabolites (11 acylcarnitines, 39 NEFA, 12 sphingomyelins (SMs), 56 phosphatidylcholines and nine lysophosphatidylcholines) using MS in participants from the German Diabetes Study baseline cohort recently diagnosed with type 1 (
n
= 100) and type 2 diabetes (
n
= 206). Four time-domain HRV indices (number of normal-to-normal (NN) intervals >50 ms divided by the number of all NN intervals pNN50; root mean square of successive differences RMSSD; SD of NN intervals SDNN; and SD of differences between adjacent NN intervals) and three frequency-domain HRV indices (very-low-frequency VLF, low-frequency LF and high-frequency HF power spectrum) were computed from NN intervals recorded during a 3 h hyperinsulinaemic–euglycaemic clamp at baseline and in subsets of participants with type 1 (
n
= 60) and type 2 diabetes (
n
= 95) after 5 years.
Results
In participants with type 2 diabetes, after Bonferroni correction and rigorous adjustment, SDNN was inversely associated with higher levels of diacyl-phosphatidylcholine (PCaa) C32:0, PCaa C34:1, acyl-alkyl-phosphatidylcholine (PCae) C36:0, SM C16:0 and SM C16:1. SD of differences between NN intervals was inversely associated with PCaa C32:0, PCaa C34:1, PCaa C34:2, PCae C36:0 and SM C16:1, and RMSSD with PCae C36:0. For VLF power, inverse associations were found with PCaa C30:0, PCaa C32:0, PCaa C32:1, PCaa C34:2 and SM C16:1, and for LF power inverse associations were found with PCaa C32:0 and SM C16:1 (
r
= −0.242 to
r
= −0.349;
p
≤ 0.0005 for all correlations). In contrast, no associations of lipid metabolites with measures of cardiac autonomic function were noted in participants recently diagnosed with type 1 diabetes. After 5 years, HRV declined due to ageing rather than diabetes, whereby prediction analyses for lipid metabolites were hampered.
Conclusions/interpretation
Higher plasma levels of specific lipid metabolites are closely linked to cardiac autonomic dysfunction in recent-onset type 2 diabetes but not type 1 diabetes, suggesting a role for perturbed lipid metabolism in the early development of CAN in type 2 diabetes.
Graphical abstract
Nonalcoholic fatty liver disease is associated with hepatic insulin resistance and may result primarily from increased hepatic de novo lipogenesis (PRIM) or secondarily from adipose tissue lipolysis ...(SEC). We studied mice with hepatocyte- or adipocyte-specific SREBP-1c overexpression as models of PRIM and SEC. PRIM mice featured increased lipogenic gene expression in the liver and adipose tissue. Their selective, liver-specific insulin resistance was associated with increased C18:1-diacylglycerol content and protein kinase Cε translocation. SEC mice had decreased lipogenesis mediated by hepatic cholesterol responsive element-binding protein and featured portal/lobular inflammation along with total, whole-body insulin resistance. Hepatic mitochondrial respiration transiently increased and declined with aging along with higher muscle reactive oxygen species production. In conclusion, hepatic insulin resistance originates from lipotoxicity but not from lower mitochondrial capacity, which can even transiently adapt to increased peripheral lipolysis. Peripheral insulin resistance is prevented during increased hepatic lipogenesis only if adipose tissue lipid storage capacity is preserved.
The rs738409(G) single nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (
) gene associates with increased risk and progression of nonalcoholic fatty liver disease ...(NAFLD). As the recently described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (hepatocellular lipids HCL) and insulin sensitivity in recent-onset diabetes.
A total of 917 participants in the German Diabetes Study (GDS) underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution, and MRS.
The G allele associated positively with HCL (β = 0.36,
< 0.01), independent of age, sex, and BMI across the whole cohort, but not in the individual clusters. Those with SIRD exhibited lowest whole-body insulin sensitivity compared with those with severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD), and severe autoimmune diabetes (SAID) clusters (all
< 0.001). Interestingly, the SIRD group presented with higher prevalence of the rs738409(G) SNP compared with other clusters and the glucose-tolerant control group (
< 0.05). HCL was higher in the SIRD group (median 13.6% 1st quartile 5.8; 3rd quartile 19.1 compared with the MOD (6.4 % 2.1; 12.4,
< 0.05), MARD (3.0% 1.0; 7.9,
< 0.001), SAID (0.4% 0.0; 1.5,
< 0.001), and glucose-tolerant (0.9% 0.4; 4.9),
< 0.001) group. Although the
polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G-allele carriers had higher circulating free fatty acid concentrations and greater adipose tissue insulin resistance compared with noncarriers (both
< 0.001).
Members of the SIRD cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.
The pathogenesis of fatty liver is not understood in detail, but lipid overflow as well as de novo lipogenesis (DNL) seem to be the key points of hepatocyte accumulation of lipids. One key ...transcription factor in DNL is sterol regulatory element-binding protein (SREBP)-1c. We generated mice with liver-specific over-expression of mature human SREBP-1c under control of the albumin promoter and a liver-specific enhancer (alb-SREBP-1c) to analyze systemic perturbations caused by this distinct alteration. SREBP-1c targets specific genes and causes key enzymes in DNL and lipid metabolism to be up-regulated. The alb-SREBP-1c mice developed hepatic lipid accumulation featuring a fatty liver by the age of 24 weeks under normocaloric nutrition. On a molecular level, clinical parameters and lipid-profiles varied according to the fatty liver phenotype. The desaturation index was increased compared to wild type mice. In liver, fatty acids (FA) were increased by 50% (p<0.01) and lipid composition was shifted to mono unsaturated FA, whereas lipid profile in adipose tissue or serum was not altered. Serum analyses revealed a ∼2-fold (p<0.01) increase in triglycerides and free fatty acids, and a ∼3-fold (p<0.01) increase in insulin levels, indicating insulin resistance; however, no significant cytokine profile alterations have been determined. Interestingly and unexpectedly, mice also developed adipositas with considerably increased visceral adipose tissue, although calorie intake was not different compared to control mice. In conclusion, the alb-SREBP-1c mouse model allowed the elucidation of the systemic impact of SREBP-1c as a central regulator of lipid metabolism in vivo and also demonstrated that the liver is a more active player in metabolic diseases such as visceral obesity and insulin resistance.
Aims/hypothesis
The aim of this study was to investigate the modifying effect of the glucose transporter (GLUT2) gene
SLC2A2
(rs8192675) variant on the glycaemic response to metformin in individuals ...recently diagnosed with type 2 diabetes.
Methods
Individuals with type 2 diabetes (
n
= 508) from the prospective German Diabetes Study (age mean ± SD 53 ± 10 years; 65% male; BMI 32 ± 6 kg/m
2
, metformin use 57%) underwent detailed metabolic characterisation (hyperinsulinaemic–euglycaemic clamp, IVGTT) during the first year after diagnosis. Participants provided self-reported data from the time of diagnosis. The change in fasting glucose was assessed in relation to
SLC2A2
genotype and glucose-lowering treatment using two-way ANCOVA with gene×treatment interactions adjusted for age, sex, BMI and diabetes duration.
Results
The C variant allele of rs8192675 was associated with a higher prevalence of diabetes symptoms at diabetes diagnosis. In the metformin monotherapy group only, patients with a C allele showed a larger adjusted blood glucose reduction during the first year after diabetes diagnosis than patients with the TT genotype (6.3 mmol/l vs 3.9 mmol/l; genotype difference 2.4 mmol/l,
p
= 0.02;
p
value for genotype interaction metformin monotherapy vs non-pharmacological therapy <0.01). The greater decline in fasting glucose (CC/CT vs TT) in metformin monotherapy persisted after further adjusting for glucose values at diagnosis (genotype difference 1.0 mmol/l,
p
= 0.01; genotype×treatment interaction
p
= 0.06).
Conclusions/interpretation
The variant rs8192675 in the
SLC2A2
gene (C allele) is associated with an improved glucose response to metformin monotherapy during the first year after diagnosis in type 2 diabetes.
Trial registration
ClinicalTrials.gov
NCT01055093
Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined ...for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein acts inhibitory on HDAC classes I/II as enzymatic inhibitor. Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent protein stabilization of p53 under normoxic but not hypoxic conditions. Functionally, Rhein inhibited collagen contraction, indicating anti-fibrotic property in cardiac remodeling. This was accompanied by increased abundance of SMAD7, but not SMAD2/3, and consistently SMAD-specific E3 ubiquitin ligase SMURF2. In conclusion, this study identifies Rhein as a novel potent direct HDAC inhibitor that may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.
Cytokine-induced signal transduction is executed by natural biological switches, which among many others control immune-related processes. Here, we show that synthetic cytokine receptors (SyCyRs) can ...induce cytokine signaling using non-physiological ligands. High-affinity GFP- and mCherry-nanobodies were fused to transmembrane and intracellular domains of the IL-6/IL-11 and IL-23 cytokine receptors gp130 and IL-12Rβ1/IL-23R, respectively. Homo- and heterodimeric GFP:mCherry fusion proteins as synthetic cytokine-like ligands were able to induce canonical signaling in vitro and in vivo. Using SyCyR ligands, we show that IL-23 receptor homodimerization results in its activation and IL-23-like signal transduction. Moreover, trimeric receptor assembly induces trans-phosphorylation among cytokine receptors with associated Janus kinases. The SyCyR technology allows biochemical analyses of transmembrane receptor signaling in vitro and in vivo, cell-specific activation through SyCyR ligands using transgenic animals and possible therapeutic regimes involving non-physiological targets during immunotherapy.
The skeletal muscle is a metabolically active tissue that secretes various proteins. These so-called myokines have been proposed to affect muscle physiology and to exert systemic effects on other ...tissues and organs. Yet, changes in the secretory profile may participate in the pathophysiology of metabolic diseases. The present study aimed at characterizing the secretome of differentiated primary human skeletal muscle cells (hSkMC) derived from healthy, adult donors combining three different mass spectrometry based non-targeted approaches as well as one antibody based method. This led to the identification of 548 non-redundant proteins in conditioned media from hSkmc. For 501 proteins, significant mRNA expression could be demonstrated. Applying stringent consecutive filtering using SignalP, SecretomeP and ER_retention signal databases, 305 proteins were assigned as potential myokines of which 12 proteins containing a secretory signal peptide were not previously described. This comprehensive profiling study of the human skeletal muscle secretome expands our knowledge of the composition of the human myokinome and may contribute to our understanding of the role of myokines in multiple biological processes. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.
•Proteomic profiling identified 548 proteins in CM of hSkMC.•Applying computational filtering assigned 305 proteins as potentially secretory.•Combined proteomic profiling identified 12 novel myokines.
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