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.

Menopause may trigger Alzheimer’s disease

Menopause may trigger Alzheimer’s disease

A new study highlights the metabolic changes that occur in the brains of menopausal and perimenopausal women, suggesting that a loss of estrogen could make these women vulnerable to developing Alzheimer’s disease.
Dr. Lisa Mosconi, from Weill Cornell Medicine, is the lead author of the study, and the findings were published in the journal PLoS One.
As Dr. Mosconi and her colleagues explain, after old age, being female is the second most major risk factor for developing Alzheimer’s disease.
Although the mechanisms responsible for this increased risk are not yet known, previous research has hinted at the transition to menopause as a potential key.
As the authors explain, this transition also involves neurological and metabolical changes. So, Dr. Mosconi and team decided to investigate these transformations.
The study found that the perimenopausal and postmenopausal women had significantly lower glucose metabolism levels than those who were premenopausal.
Brain cells have estrogen receptors, they explain, and a drop in estrogen levels may cause a “starvation reaction” in these cells. Such a metabolic state can lead to brain cell dysfunction.
It also means the loss of a key neuroprotective element in the female brain and a higher vulnerability to brain aging and Alzheimer’s disease.”

Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA)

Non-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA)

Hepatic mitochondria play a central role in the regulation of intermediary metabolism and maintenance of normoglycemia, and there is great interest in assessing rates of hepatic mitochondrial citrate synthase flux (VCS) and pyruvate carboxylase flux (VPC) in vivo.
A key motivation for this study is to develop an alternative non-invasive tracer method to model hepatic metabolism in vivo with minimal perturbation of hepatic mitochondrial metabolism.
To validate this method, we performed independent cross-validation studies and observed an excellent correlation (P < 10−15, R2 = 0.99) between VPC/VCS calculated using PINTA and our previous ex vivo NMR tracer technique in rats9, 10, and similar VPC/VCS ratios measured in healthy human subjects using two independent tracer methods (infusion of [3-13C]lactate or [1-13C]acetate1, 2). Validation studies demonstrate the ability of the PINTA method to measure an increase in VCS flux following treatment with a controlled-release mitochondrial protonophore (CRMP), which promoted liver-targeted mitochondrial uncoupling11 and an increase in the VPC/VEGP ratio after an extended fast. We then measured the VPC/VCS ratio in three healthy human subjects following a 12 h overnight fast, and found that the two methods (in vivo NMR analysis of positional glutamate enrichment1 or PINTA analysis of plasma glucose) gave similar results, with VPC/VCS ~ 1.5–1.9 using both methods (Fig. We then measured the VPC/VEGP ratio in glycogen-depleted rats fasted for 48 h and compared the VPC/VEGP flux ratio to rats that had fasted for just 6 h, after a prior fast and refeeding to increase liver glycogen content similar to the recently-fed state (Supplementary Fig. PINTA measurements demonstrated that VPC/VEGP increased six-fold in hepatic glycogen-depleted rats fasted for 48 h, with the percentage of glucose production from pyruvate carboxylase flux increasing from ~13 to ~80% (Fig.

A Novel Mouse Model of iNKT Cell-deficiency Generated by CRISPR/Cas9 Reveals a Pathogenic Role of iNKT Cells in Metabolic Disease

A Novel Mouse Model of iNKT Cell-deficiency Generated by CRISPR/Cas9 Reveals a Pathogenic Role of iNKT Cells in Metabolic Disease

All four Traj18-partial deletion mouse lines harbored similar Traj gene segments as WT B6 mice, except for Traj18 (Fig.
(a) TCRα repertoire diversity analyzed by next generation sequencing.
Frequencies of iNKT cells in the spleen and liver from WT B6 and Traj18−/− (1-1 L) mice were analyzed by flow cytometry, which revealed iNKT cell-deficiency in Traj18−/− (1-1 L) mice (Fig. Analysis of developmental stages of thymocytes revealed no difference between Traj18−/− (1-1 L) and WT B6 mice (Supplemental Fig. We also analyzed the frequencies of T cells with specific functions such as type 2 NKT cells, regulatory T cells (Treg) and mucosal-associated invariant T (MAIT) cells in the thymus, resulting in no differences between Traj18−/− (1-1 L) and WT B6 mice (Supplemental Fig.
Because some functional studies on iNKT cells require animals on a genetic background distinct from the B6 strain, we also generated a Traj18−/− (1-1 L) BALB/c mouse line by backcrossing, and confirmed the absence of iNKT cells and cytokine production in response to α-GalCer stimulation (Supplemental Fig.
However, divergent findings for the metabolic role of iNKT cells have been reported in studies using the previously generated Traj18−/− mouse strain.
Among the experimental groups on HFD, both Traj18−/− (1-1 L) and Cd1d−/− mice gained less weight than WT B6 mice, whereas there was no significant difference in the weight gain between Traj18−/− (1-1 L) and Cd1d−/− mice (Fig.
Another new Traj18−/− mouse line generated by Dashtsoodol et al. also contained similar Trav1-Traj33 expression levels as WT B6 mice13, indicating normal MAIT cell development and cell number.

Gut fungi may hold key to metabolic health

Gut fungi may hold key to metabolic health

As Dr. Gale and her colleagues explain, previous research has shown that obesity is associated with changes in gut bacteria.
Most studies have therefore focused on how a high-fat diet alters the gut microbiome, leaving the role of gut fungi overlooked.
The new study aims to fill this gap in research, particularly since gut fungi have recently been shown to affect intestinal inflammation.
Having analyzed the bacterial and fungal microbiota, the researchers found that the mice fed the high-fat diet had “significantly different” bacterial and fungal compositions than those fed a normal diet.
Regarding fungi, the researchers found that the mice fed a standard diet had an increase in six fungal taxa.
Dr. Gale notes that the role of fungi in understanding obesity has been neglected in the research community, and that the available study methods should reflect the need to pay more attention to fungi. “The methods development hasn’t caught up to where it is with bacteria. “We really need to be looking at all the microbes and how they are interacting with each other to get a full picture of what the microbiome structure and function is in a given individual,” explains Dr. Gale.