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Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue.

ABSTRACT: OBJECTIVES:Understanding how loci identified by genome wide association studies (GWAS) contribute to pathogenesis requires new mechanistic insights. Variants within CDKAL1 are strongly linked to an increased risk of developing type 2 diabetes and obesity. Investigations in mouse models have focused on the function of Cdkal1 as a tRNALys modifier and downstream effects of Cdkal1 loss on pro-insulin translational fidelity in pancreatic ?-cells. However, Cdkal1 is broadly expressed in other metabolically relevant tissues, including adipose tissue. In addition, the Cdkal1 homolog Cdk5rap1 regulates mitochondrial protein translation and mitochondrial function in skeletal muscle. We tested whether adipocyte-specific Cdkal1 deletion alters systemic glucose homeostasis or adipose mitochondrial function independently of its effects on pro-insulin translation and insulin secretion. METHODS:We measured mRNA levels of type 2 diabetes GWAS genes, including Cdkal1, in adipose tissue from lean and obese mice. We then established a mouse model with adipocyte-specific Cdkal1 deletion. We examined the effects of adipose Cdkal1 deletion using indirect calorimetry on mice during a cold temperature challenge, as well as by measuring cellular and mitochondrial respiration in vitro. We also examined brown adipose tissue (BAT) mitochondrial morphology by electron microscopy. Utilizing co-immunoprecipitation followed by mass spectrometry, we performed interaction mapping to identify new CDKAL1 binding partners. Furthermore, we tested whether Cdkal1 loss in adipose tissue affects total protein levels or accurate Lys incorporation by tRNALys using quantitative mass spectrometry. RESULTS:We found that Cdkal1 mRNA levels are reduced in adipose tissue of obese mice. Using adipose-specific Cdkal1 KO mice (A-KO), we demonstrated that mitochondrial function is impaired in primary differentiated brown adipocytes and in isolated mitochondria from A-KO brown adipose tissue. A-KO mice displayed decreased energy expenditure during 4 °C cold challenge. Furthermore, mitochondrial morphology was highly abnormal in A-KO BAT. Surprisingly, we found that lysine codon representation was unchanged in Cdkal1 A-KO adipose tissue. We identified novel protein interactors of CDKAL1, including SLC25A4/ANT1, an inner mitochondrial membrane ADP/ATP translocator. ANT proteins can account for the UCP1-independent basal proton leak in BAT mitochondria. Cdkal1 A-KO mice had increased ANT1 protein levels in their white adipose tissue. CONCLUSIONS:Cdkal1 is necessary for normal mitochondrial morphology and function in adipose tissue. These results suggest that the type 2 diabetes susceptibility gene CDKAL1 has novel functions in regulating mitochondrial activity.

SUBMITTER: Palmer CJ

PROVIDER: S-EPMC5641635 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue.

Palmer Colin J CJ Bruckner Raphael J RJ Paulo Joao A JA Kazak Lawrence L Long Jonathan Z JZ Mina Amir I AI Deng Zhaoming Z LeClair Katherine B KB Hall Jessica A JA Hong Shangyu S Zushin Peter-James H PH Smith Kyle L KL Gygi Steven P SP Hagen Susan S Cohen David E DE Banks Alexander S AS

Molecular metabolism 20170731 10

<h4>Objectives</h4>Understanding how loci identified by genome wide association studies (GWAS) contribute to pathogenesis requires new mechanistic insights. Variants within CDKAL1 are strongly linked to an increased risk of developing type 2 diabetes and obesity. Investigations in mouse models have focused on the function of Cdkal1 as a tRNA<sup>Lys</sup> modifier and downstream effects of Cdkal1 loss on pro-insulin translational fidelity in pancreatic β-cells. However, Cdkal1 is broadly express ...[more]

PMID: 29031721

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Project description:Perivascular adipose tissue (PVAT) regulates vascular function by secreting vasoactive substances. In mice, Notch signaling is activated in the PVAT during diet-induced obesity, and leads to the loss of the thermogenic phenotype and adipocyte whitening due to increased lipid accumulation. We used the Adiponectin-Cre (Adipoq-Cre) strain to activate a ligand-independent Notch1 intracellular domain transgene (N1ICD) to drive constitutive Notch signaling in the adipose tissues (N1ICD;Adipoq-Cre). We previously found that constitutive activation of Notch1 signaling in the PVAT phenocopied the effects of diet-induced obesity. To understand the downstream pathways activated by Notch signaling, we performed a proteomic analysis of the PVAT from control versus N1ICD;Adipoq-Cre mice. This comparison identified prominent changes in the protein signatures related to metabolism, adipocyte homeostasis, mitochondrial function, and ferroptosis. PVAT-derived stromal vascular fraction cells were derived from our mouse strains to study the cellular and molecular phenotypes during adipogenic induction. We found that cells with activated Notch signaling displayed decreased mitochondrial respiration despite similar levels of adipogenesis and mitochondrial number. We observed variable regulation of the proteins related to mitochondrial dynamics and ferroptosis, including PHB3, PINK1, pDRP1, and the phospholipid hydroperoxidase GPX4. Mitochondria regulate some forms of ferroptosis, which is a regulated process of cell death driven by lipid peroxidation. Accordingly, we found that Notch activation promoted lipid peroxidation and ferroptosis in PVAT-derived adipocytes. Because the PVAT phenotype is a regulator of vascular reactivity, we tested the effect of Notch activation in PVAT on vasoreactivity using wire myography. The aortae from the N1ICD;Adipoq-Cre mice had increased vasocontraction and decreased vasorelaxation in a PVAT-dependent and age-dependent manner. Our data provide support for the novel concept that increased Notch signaling in the adipose tissue leads to PVAT whitening, impaired mitochondrial function, increased ferroptosis, and loss of a protective vasodilatory signal. Our study advances our understanding of how Notch signaling in adipocytes affects mitochondrial dynamics, which impacts vascular physiology.

Project description:BackgroundDiabetes is one of the common chronic diseases in which susceptibility is determined by a combination of genetic and environmental factors, and more than 90% of diabetic patients are diabetes mellitus type 2 (T2DM). The existing studies on the association between CDKAL1 rs10946398 gene polymorphism and susceptibility to type 2 diabetes are inconsistent across populations.AimWe aim to explore the association between CDKAL1 rs10946398 gene polymorphism and susceptibility to type 2 diabetes in different populations.MethodsWe examined all studies before June 12, 2021, that associated CDKAL1 rs10946398 with T2DM. Heterogeneity was assessed by meta-analysis of allelic inheritance models (A vs. C), dominant inheritance models (AA vs. AC+CC), and recessive inheritance model (AA+AC vs. CC); I 2 was used to assess the heterogeneity (if I 2 < 50%, the fixed-effects model was used; if I 2 ≥ 50%, the random-effects model was used for data consolidation); correlation was judged by a forest map; potential publication bias was tested by the Egger test (p > 0.05 indicates that there is no publication bias).ResultsFourteen data totaling 30288 subjects, including 19272 controls and 11016 patients with T2DM, met our inclusion criteria. In the Asian population, the differences were statistically significant (p < 0.01) for dominant genetic model (OR = 0.75, 95%CI = 0.64-0.88, p = 0.0003). But the allelic effect model (OR = 0.87, 95%CI = 0.75-1.02, p = 0.08) and the recessive genetic model (OR = 0.85, 95%CI = 0.66-1.10, p = 0.23) were not statistically significant (p > 0.01). In the non-Asian population, the differences were statistically significant (p < 0.01) for the allelic effect model (OR = 0.83, 95%CI = 0.77-0.88, p < 0.00001), the dominant model (OR = 0.79, 95%CI = 0.72-0.87, p < 0.00001), and the recessive model (OR = 0.78, 95%CI = 0.70-0.87, p < 0.0001).ConclusionIn this study, CDKAL1 RS10946398 was positively associated with T2DM, but the association was different in Asian populations.

Project description:IntroductionCurrent study aimed to find the association of genes polymorphism of CDKAL1, HHEX, CDKN2A/2B, and IGF2BP2 with type 2 diabetes (T2DM) in the population of Uttarakhand.Research design and methodsOverall 469 persons comprising 369 recently diagnosed T2DM cases and 100 healthy control were enrolled in the present study. The polymorphisms were analyzed through the PCR-RFLP technique.ResultsFor the rs10440833 variant (CDKAL1), CC genotype's frequency was significantly high among T2DM subjects than controls and increase the T2DM risk (OR: 4.46, 95% CI: 2.22-8.99, p <0.0001). The c allele was significantly found to increase the T2DM risk (OR: 2.20, 95% CI: 1.54-3.14, p <0.001). In the rs1111875 variant (HHEX), the difference of genotype frequencies among T2DM cases and control was statistically non-significant (p-0.138). We did not observe significant differences in allelic frequencies among T2DM cases and control (p-0.444). In the case of rs10811661 variant (CDKN2A/2B), frequency of both TC (OR: 3.16, 95% CI: 1.84-5.42, p <0.0001) and TT (OR: 5.84, 95% CI: 1.75-19.45, p -0.004) genotype were significantly higher in T2DM cases in comparison with control and significantly associated with higher T2DM risk. Compared to the C allele, a significant increase in T2DM risk was documented with the T allele (OR: 2.47, 95% CI: 1.55-3.92, p <0.001). For rs4402960 variant (IGF2BP2), TT genotype contributed to increased T2DM risk (OR: 4.25, 95% CI: 2.02-8.93, p -0.0001). T allele's frequency was significantly high in T2DM cases in comparison with healthy control. Except WHR, HDL-C, exercise, household chores, standing work more than 3 hours, and family history, significant differences were found between T2DM cases and healthy individuals in all other parameters.ConclusionOur study concluded a significant association of CDKAL1, CDKN2A/2B, and IGF2BP2 polymorphism with T2DM in the Uttarakhand population. For HHEX, the genotype and allelic frequencies difference between T2DM cases and control were statistically non-significant. However, a significant association of HHEX gene polymorphism with T2DM was observed only under the dominant model.

Project description:CONTEXT/OBJECTIVE:Impaired adipose tissue (AT) function might induce recent-onset type 2 diabetes (T2D). Understanding AT energy metabolism could yield novel targets for the treatment of T2D. DESIGN/PATIENTS:Male patients with recently-diagnosed T2D and healthy male controls (CON) of similar abdominal subcutaneous AT (SAT)-thickness, fat mass, and age (n?=?14 each), underwent hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose and indirect calorimetry. We assessed mitochondrial efficiency (coupling: state 3/4o; proton leak: state 4o/u) via high-resolution respirometry in superficial (SSAT) and deep (DSAT) SAT-biopsies, hepatocellular lipids (HCL) and fat mass by proton-magnetic-resonance-spectroscopy and -imaging. RESULTS:T2D patients (known diabetes duration: 2.5 [0.1; 5.0] years) had 43%, 44%, and 63% lower muscle insulin sensitivity (IS), metabolic flexibility (P?<?0.01) and AT IS (P?<?0.05), 73% and 31% higher HCL (P?<?0.05), and DSAT-thickness (P?<?0.001), but similar hepatic IS compared with CON. Mitochondrial efficiency was ~22% lower in SSAT and DSAT of T2D patients (P?<?0.001) and ~8% lower in SSAT vs DSAT (P?<?0.05). In both fat depots, mitochondrial coupling correlated positively with muscle IS and metabolic flexibility (r ? 0.40; P?<?0.05), proton leak correlated positively (r ? 0.51; P?<?0.01) and oxidative capacity negatively (r ? -0.47; P?<?0.05) with fasting free fatty acids (FFA). Metabolic flexibility correlated positively with SAT-oxidative capacity (r ? 0.48; P?<?0.05) and negatively with DSAT-thickness (r = -0.48; P?<?0.05). DSAT-thickness correlated negatively with mitochondrial coupling in both depots (r ? -0.50; P?<?0.01) and muscle IS (r = -0.59; P?<?0.01), positively with FFA during clamp (r?=?0.63; P?<?0.001) and HCL (r?=?0.49; P?<?0.01). CONCLUSIONS:Impaired mitochondrial function, insulin resistance, and DSAT expansion are AT abnormalities in recent-onset T2D that might promote whole-body insulin resistance and increased substrate flux to the liver.

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Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue.

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Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue.

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