Diabetes for Researchers

Depletion of Prmt1 in adipocytes impairs glucose homeostasis in diet-induced obesity

Protein arginine methyltransferase (PRMT) 1 is involved in the regulation of various metabolic pathways such as glucose metabolism in liver and atrophy in the skeletal muscle. However, the role of PRMT1 in the fat tissues under the disease state has not been elucidated to date.

Here, we delineate the function of this protein in adipocytes in vivo. PRMT1 expression was abundant in the white adipose tissues (WAT), which was induced upon high fat diet in mice as well as by obesity in humans. We found that adipocyte-specific depletion of Prmt1 resulted in the decreased fat mass without overall changes in body weight in mice. Mechanistically, the depletion of Prmt1 in WAT led to the activation of AMPK pathway, which was causal to the increased lipophagy, mitochondrial lipid catabolism and the resultant reduction in lipid droplet size in WAT in vivo. Interestingly, in spite of the increased energy expenditure, we observed a promotion of adipose tissue inflammation and an ectopic accumulation of triglycerides in the peripheral tissues in Prmt1 adipocyte-specific knockout mice, which promoted the impaired insulin tolerance that is reminiscent of mouse models of lipodystrophy. These data collectively suggest that PRMT1 prevents WAT from excessive degradation of triglycerides by limiting AMPK-mediated lipid catabolism to control whole body metabolic homeostasis in diet-induced obesity conditions.

Read More

The attenuation of diabetic nephropathy by annexin A1 via regulation of lipid metabolism through AMPK/PPAR{alpha}/CPT1b pathway

Inflammation and abnormal metabolism play important roles in the pathogenesis of diabetic nephropathy (DN). Annexin A1 (ANXA1) contributes to inflammation resolution and improves metabolism. Here, we assess the effects of ANXA1 in diabetic mice and proximal tubular epithelial cells (PTECs) treated with high glucose plus palmitate acid (HGPA), and explore the association of ANXA1 with lipid accumulation in DN patients. It is found that ANXA1 deletion aggravates renal injuries, including albuminuria, mesangial matrix expansion and tubulointerstitial lesions in HFD/STZ-induced diabetic mice. ANXA1 deficiency promotes intra-renal lipid accumulation and drives mitochondrial alterations in kidneys. In addition, Ac2-26, an ANXA1 mimetic peptide, has a therapeutic effect against lipid toxicity in diabetic mice. In HGPA-treated human PTECs, ANXA1 silencing causes FPR2/ALX-driven deleterious effects, which suppress phosphorylated Thr172AMPK, resulting in decreased PPARα and CPT1b expression and increased HGPA-induced lipid accumulation, apoptosis and elevated expression of pro-inflammatory and pro-fibrotic genes. Last but not least, the extent of lipid accumulation correlates with renal function, and the level of tubulointerstitial ANXA1 expression correlates with ectopic lipid deposition in kidneys of DN patients. These data demonstrate that ANXA1 regulates lipid metabolism of PTECs to ameliorate disease progression, hence it holds great potential as a therapeutic target for DN.

Read More

Hijacking Dorsal Raphe to Improve Metabolism and Depression-like Behaviors via BDNF Gene Transfer in Mice

Moods and metabolism modulate each other. High comorbidity of depression and metabolic disorders such as diabetes and obesity poses a great challenge to treat such condition. Here we report the therapeutic efficacy of brain-derived neurotrophic factor (BDNF) by gene transfer in the dorsal raphe nucleus (DRN) in a chronic unpredictable mild stress model of depression (CUMS) and models of diabetes and obesity. In CUMS, BDNF-expressing mice displayed antidepressant- and anxiolytic-like behaviors, which are associated with augmented serotonergic activity. Both in the diet-induced obesity model (DIO) and in db/db mice, BDNF ameliorated obesity and diabetes, which may be mediated by enhanced sympathetic activity, not involving DRN serotonin. Chronic activation of DRN neurons via chemogenetic tools produced similar effects as BDNF in DIO mice. These results established the DRN as a key nexus in regulating depression-like behaviors and metabolism, which can be exploited to combat comorbid depression and metabolic disorders via BDNF gene transfer.

Read More

Adipocyte-specific deletion of lamin A/C largely models human familial partial lipodystrophy type 2

Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate function of lamin A/C in adipose tissues, we created mice with an adipocyte-specific loss of Lmna (LmnaADKO). Although LmnaADKO mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. LmnaADKO mice exhibit a surprisingly mild metabolic dysfunction on a chow diet, but on a high fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas LmnaADKO mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared to controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully-differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. LmnaADKO mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.

Read More

Tolerogenic Dendritic Cells Shape a Transmissible Gut Microbiota that Protects from Metabolic Diseases

Excess of chronic contact between microbial motifs and intestinal immune cells are known to trigger a low-grade inflammation involved in many pathologies such as obesity and diabetes.

The important skewing of intestinal adaptive immunity in the context of diet-induced obesity (DIO) is well described but how dendritic cells (DCs) participate to these changes is still poorly documented. To address this question, transgenic mice with enhanced DCs lifespan and immunogenicity (DChBcl-2 mice) are challenged with a high-fat diet.

Those mice display resistance to DIO and metabolic alterations. The DIO-resistant phenotype is associated with healthier parameters of intestinal barrier function and lower intestinal inflammation. DChBcl-2 DIO-resistant mice demonstrate a particular increase in tolerogenic DC numbers and function which is associated with strong intestinal IgA, Th17, and T regulatory immune responses.

Microbiota composition and function analyses reveal that the DChBcl-2 mice microbiota is characterized by lower immunogenicity and enhanced butyrate production. Cohousing experiments and fecal microbial transplantations are sufficient to transfer the DIO resistance status to WT mice demonstrating that maintenance of DCs tolerogenic ability sustains a microbiota able to drive DIO resistance. DCs tolerogenic function is revealed as a new potent target in metabolic disease management.

Read More