The weekly science round up – 5 April

Actually, some of  the papers already came out last week, but only just got round to having a proper look at them.

Science

Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex (Castellano et al.)

Copied from the final bit of the paper: “This work identifies dedicated machinery that couples cholesterol trafficking through the lyso- some to regulation of cellular growth signaling. LDL-derived cholesterol affects mTORC1 through the combined action of a positive regulator, SLC38A9, and a negative regulator, NPC1 (Fig. 4G). SLC38A9 conveys increases in lysosomal cholesterol through its conserved CARC and CRAC motifs, leading to lysosomal recruitment and activation of mTORC1. In contrast, NPC1 associates with the mTORC1 scaffolding complex and translates cholesterol depletion into mTORC1 inhibition.”

Nature

Structural insights into adiponectin receptors suggest ceramidase activity (Vasiliauskaité-Brooks et al.)

Discovery that ADIPORs (1+2) have ceramidase activity that can be enhanced upon adiponectin stimulation. Overall, this enzymatic activity is low so future studies are required to understand whether it bears relevance to the function of adiponectin in vivo and its link to metabolic improvements.

 

The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue (Lynes et al.) 

Cold-induced activation of brown adipose tissue (BAT) is known to result in increased energy expenditure, and it is believed that BAT energy expenditure can be harnessed therapeutically in metabolic disorders. Using global lipodmics, this study identifies a BAT-specific lipokine 12,13-diHOME which is released in response to cold exposure and activates BAT fuel utilisation. Consistent with a decrease in BAT mass with obesity, 12,13-diHOME levels were negatively correlated with obesity and other phenotypes characteristic of the metabolic syndrome. It is impressive that this lipokine is first identified in human participants exposed to cold, followed by mechanistic studies in mouse models, where the effects of 12,13-diHOME on free fatty acid uptake are comparable to noradrenaline-mediated BAT activation. Overall, an elegant study advancing the field with a new candidate for pharmacologic BAT activation.

 

Nature Biotechnology

Large-scale design of robust genetic circuits with multiple inputs and outputs for mammalian cells (Weinberg et al.)

My brain gets mushy when I try to read this in detail at 10 pm in the evening, but just quite cool to see the engineering of one of the most sophisticated computational biological circuits to date. This done by combining orthogonal recombinases and various DNA sequences that control transcription. Again, I think an electrical engineer would understand this paper better than me, but still impressive…

Synergistic drug combinations for cancer identified in a crisPr screen for pairwise genetic interactions (Han et al.)

In this paper, a global CRISPR screen is performed to identify combinatorial interactions between cancer drug targets. 490,000 sgRNAs are used to screen for synthetic lethal drug target pairs in K562 leukemia cells. The approach is interesting and applicable to other areas. Worth noting the technical aspects of the screen.

A similar paper has also been published in Nature Methods: Combinatorial CRISPR–Cas9 screens for de novomapping of genetic interactions (Shen et al.)

Nature Protocols

From the Zhang lab on CRISPR screens: Genome-scale CRISPR-Cas9 knockout and transcriptional activation screening (Joung et al.)

 

Nature Genetics

Estimating the selective effects of heterozygous protein-truncating variants from human exome data (Cassa et al.)

Not the best person to understand this, but a study that looks at protein truncating variatns in ExAC if they are predicted to be consequential and estimates gene-based fitness effects and individual gene fitness cost in heterozygotes (only using data from individuals with non-Mendelian disorders). Basically useful to look at novel genes that might have important functions in development as mutations would be highly selected against. The mTOR and MAPK pathways are in the list of pathways with genes that seem to have a high gene fitness cost (unsurprising).

Nature Chemical Biology

Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase (Stanford et al.)

Worth a read – actually quite metabolic and signalling-relevant. Here is the abstract:

“Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.”

JCI Insight

Insulin’s direct hepatic effect explains the inhibition of glucose production caused by insulin secretion (Edgerton et al.)

Given the redundancy in insulin’s ability to control hepatic glucose production (direct and indirect mechanisms), this study set out to explore the contextual importance of some of these mechanisms.

An interesting excerpt from the introduction of the paper, discussing the physiological difference between peripheral insulin infusion and direct infusion into the portal vein: “It is apparent, therefore, that when insulin is infused into a peripheral vein its direct effects on the liver are underemphasized, while its indirect effects are exaggerated. Thus, the route of insulin delivery can have a major impact on both the overall response of the liver and the mechanisms by which that response is achieved. Indeed, over a range of insulin doses, peripheral insulin infusion was not as effective at suppressing HGP as compared with direct infusion into the portal vein.”

Based on this information, “the purpose of this study was to assess whether insulin’s acute indirect effects on HGP are additive to, redundant to, or synergistic with its direct hepatic effects, in the context of a physiologic increase in portal vein insulin level in a large animal model. The impact of eliminating each of insulin’s indirect effects, either alone or in combination, was determined. We focused on insulin’s ability to lower FFAs, activate brain insulin signaling, and reduce glucagon secretion since recent studies have concluded that suppression of lipolysis is the major mechanism by which insulin suppresses HGP (11), that increased brain insulin action is required for the rapid suppression of HGP (17), and because a fall in plasma gluca- gon is potentially a powerful contributor to insulin’s ability to inhibit HGP (15).”

They perform portal insulin infusion (in mice) and simulate a 6-fold increase in insulin secretion, but manage to maintain the physiologic insulin gradient between liver and the rest of the body.

This paper is very interesting given the multiple demonstrations of a key role of insulin’s indirect effect on HGP via modulation of FFA release from adipose tissue; in contrast, this study seems to imply that FFA don’t play a role in HGP suppression under what is described as more physiologic conditions. Similarly, a fall in glucagon secretion is not necessary for insulin direct ability to suppress HGP. The same is true when insulin’s brain action is inhibited. The discussion is really worth a read!

EMBO Journal

AKT-phosphorylated FOXO1 suppresses ERK activation and chemoresistance by disrupting IQGAP1-MAPK interaction (Pan et al.)

Looking forward to reading this one at some point! The accompanying News and Views sums it all up: “And Akt-ion! IQGAP1 in control of signaling pathways” (Choi et al.

Mfn2 is critical for brown adipose tissue thermogenic function (Boutant et al.)

Worth a read! Adipose tissue-specific KO of Mfn2 results in increased fat accumulation in BAT even on a low-fat diet as well as an overall decrease in energy expenditure and an inability to sustain normal body temperature via cold-induced BAT thermogenesis. This is linked to an impaired O2 flux in BAT when specifically measuring the different complexes forming the electron transport chain. At the protein level, Complex I is almost absent upon Mfn2 ablation. Mfn2 is shown to interact with perilipin and the data suggest that this enhances mitochondria-lipid droplet interactions. It seems that glycolysis is increased due to mitochondrial dysfunction. There is also an increased accumulation of FAT in subcutaneous WAT and the authors suggest that this exlpains the improved metabolic profile of HFD-fed adipose-specific Mfn2 KO mice.

USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling (Luo et al.)

Had a quick skim – in cancer cell lines and cancer mouse models, but the mechanism might be valid in a more physiological context, too. Basically, USP49 deubiquinates FKBP51 which results in increased stabilisation. In turn, FKBP51 promotes the interaction between AKT and PHLPP, which dephosphorylates AKT at S473 thereby reducing its activation.

The phosphorylation status of T522 modulates tissue-specific functions of SIRT1 in energy metabolism in mice (Lu et al.)

Just skimmed the abstract, but might be interesting to adipogenesis enthusiasts.

eLife

Angiopoietin-2 in white adipose tissue improves metabolic homeostasis through enhanced angiogenesis (An et al.) – only read abstract, but might be relevant. Just in press, so still not formatted properly, i.e. annoying to read.

Diabetes

 

 

Other exciting bits

I have been reading a lot of developmental biology recently and came across the following Guardian coverage of the first experiments that make it possible to break the 14-day rule for embryo research. I just find the videos and images amazing + the useful infographic of lineage specification at the bottom. The two papers giving rise to the Guardian feature can be found at Nature and Nature Cell Biology. These are landmark studies and were recently followed up by a study from the same Cambridge group, now demonstrating that embryonic and extra-embryonic stem cells can be assembled in vitroto mimic embryogenesis (effectively generating embryos in vitro, see Harrison et al. 2017 Science).

In terms of interesting metabolism reviews, it is worth having a look at Nature Reviews Endocrinology – there are good ones on adipose tissue etc.

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