Targeting ‘simple proteins’ may extend metabolic healthspan

Targeting ‘simple proteins’ may extend metabolic healthspan

A range of age-related metabolic diseases may be prevented by lowering the levels of certain proteins called “fatty acid-binding proteins.”
Metabolic health may be preserved well into old age, a new study suggests, if we keep fatty acid-binding protein (FABP) levels very low.
In the new study, researchers from the Harvard T.H.
Chan School of Public Health in Boston, MA, altered levels of these proteins in mice in an attempt to see whether doing so would promote metabolic health, and, implicitly, lifespan.
Chan School of Public Health, and the findings were published in the journal Cell Reports.
Why study FABPs?
The study found that insufficient FABP levels “extended metabolic healthspan, [protecting] against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease.”
But “surprisingly,” write the authors, “FABP-deficient mice did not [show] any extension of lifespan.”
In other words, the mice shared many similarities with rodents that had undergone calorie restriction.
Therefore, some of the cardiometabolic benefits of calorie restriction could be selectively replicated by targeting FABPs.

Calpain Inhibition Attenuates Adipose Tissue Inflammation and Fibrosis in Diet-induced Obese Mice

Calpain Inhibition Attenuates Adipose Tissue Inflammation and Fibrosis in Diet-induced Obese Mice

To define whether activated calpains influence diet-induced obesity and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for 16 weeks.
However, CAST overexpression significantly reduced adipocyte apoptosis, adipose tissue collagen and macrophage accumulation as detected by TUNEL, Picro Sirius and F4/80 immunostaining, respectively.
Furthermore, calpain inhibition suppressed macrophage migration to adipose tissue in vitro.
Abundance of calpain protein and its activity was increased in obese adipose tissue.
(A) Calpain-1, -2, -4, CAST and β-actin protein were detected by Western blotting in epididymal white adipose tissue (EpiWAT) extracts of wild type mice fed either a LFD or HFD for 16 weeks (n = 3).
(A) Representative TUNEL staining of EpiWAT cross-sections from 16 week LFD and HFD fed CAST WT and Tg mice.
(B) Representative EpiWAT sections from LFD and HFD fed CAST WT and Tg mice immunostained for active caspase 3.
(A) Representative immunofluorescent staining of F4/80 in EpiWAT cross-sections from 16 week LFD and HFD fed CAST WT and Tg mice.
(A) Representative Sirius red staining of EpiWAT cross-sections from LFD and HFD fed CAST WT and Tg mice.
(A) Representative hematoxylin and eosin staining of liver cross-sections from LFD and HFD fed CAST WT and Tg mice.

Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation

Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation

Moreover, elevated VLDLR protein was detected in CD11b+ ATMs from obese adipose tissues (Fig.
These data suggested that macrophage VLDLR could potentiate M1-like macrophage polarization by uptaking VLDL.
Although it has been shown that elevated circulating ceramides would confer systemic insulin resistance40, 41, the levels of secreted ceramides were not different in CM from WT and VLDLR KO BMDMs (Supplementary Fig. In WT macrophages, the level of C16:0 ceramides was elevated by VLDL, whereas VLDLR KO macrophages did not increase C16:0 ceramides in the presence of VLDL (Fig.
In the presence of VLDL, the levels of iNOS, TNFα, and IL-1β mRNA were less increased in VLDLR KO macrophages than WT macrophages (Fig.
Together, these data indicated that macrophage VLDLR could potentiate adipose tissue inflammation in DIO.
c, d Relative mRNA levels of macrophage (c) and pro-inflammatory (d) markers in EATs from WT and KO BMT mice.
These data imply that macrophage VLDLR would be important for potentiating M1-like macrophage polarization in the presence of VLDL.

HIV-1 viral protein R (Vpr) induces fatty liver in mice via LXRα and PPARα dysregulation: implications for HIV-specific pathogenesis of NAFLD

HIV-1 viral protein R (Vpr) induces fatty liver in mice via LXRα and PPARα dysregulation: implications for HIV-specific pathogenesis of NAFLD

HIV patients develop hepatic steatosis.
Vpr enhanced association of LXRα with Lxrα and Srebp1c promoters, increased LXRE-LXRα binding, and broadly altered hepatic expression of LXRα-regulated lipid metabolic genes.
(A) Immunoblots show expression of transcription factors and their target proteins in Vpr-Tg vs. WT mice (N = 4 per group).
(F) Immunoblots show expression of transcription factor and their target proteins in sVpr-treated vs. vehicle-treated mice (N = 4 per group; N = 3 per group for ACC/pACC).
Full size image Vpr binds to LXRα and enhances LXRE-dependent promoter activity.
Data are presented as means ± SE of two replicates, and are representative of two experiments.
(A) Fatty acid oxidation was decreased in liver of Vpr-Tg compared to WT mice (P = 0.006; N = 6 per group).
(C) Pparα mRNA level was decreased in liver of Vpr-Tg compared to WT mice (N = 5–6 per group).
(B) Decreased protein level of MTP was present in liver of Vpr-Tg compared to WT mice (N = 4 per group).
(A) Scatterplot of gene expression from RNA-Seq in Vpr-Tg compared with WT mouse liver.

The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPARγ

The RBM14/CoAA-interacting, long intergenic non-coding RNA Paral1 regulates adipogenesis and coactivates the nuclear receptor PPARγ

In conclusion, we have identified a novel component of the adipogenic transcriptional regulatory network defining the lincRNA Paral1 as an obesity-sensitive regulator of adipocyte differentiation and function.
(C) Paral1 transcript level in differentiating 3T3-L1 cells.
Paral1 transcript levels in indicated mouse tissues were assayed by RT-qPCR as above.
Comparing to eWAT control: *p < 0.05; **p < 0.01; ***p < 0.001. (F,G) Paral1 expression level in fractionated adipose tissues. Rplp0 and Neat1 RNA were used as cytosolic and nuclear RNA controls, respectively. Control (Ctrl-LNA) or LNA gapmers targeting Rbm14 (Rbm14-LNA, RBM14/2-LNA) were transfected at D0 and Rbm14 RNA and protein levels were assayed by RT-qPCR and western blotting as above at D8. Results are expressed as fold change relative to luciferase level detected in cells transfected without the indicated transcription factor. Results are expressed as fold change relative to luciferase level detected in cells transfected without the indicated transcription factor. (E) Paral1 and Pparγ expression in eWAT.