Cells use a little-known molecule to protect themselves from iron overload

Amazing stuff! Biological iron is no irony! 😊

Notice the charts in this study are unusually very well done. They tell a consistent story about the function of polyamines.

"... When too much of [iron] is left free inside cells, it can trigger destructive reactions that break down DNA, proteins, and even cell membranes.

Now, ... have discovered that cells rely on an unexpected protector against this threat: small molecules called polyamines.

The researchers’ detailed findings ... reveal that polyamines act like storage lockers for iron, safely holding the metal in a non-reactive state until cells need it.

These findings solve a decades-old mystery about why cells maintain such extraordinarily high levels of polyamines and uncover a previously unknown defense mechanism that protects cells from toxic iron overload. ..."

From the highlights and abstract:

"Highlights

• Genome-wide CRISPR screen identifies polyamine-GPX4 synthetic lethality

• Polyamine depletion raises labile iron and ferritin without altering total iron

• Live-cell labile iron sensor shows inverse coupling with polyamines

• Spermine and spermidine directly coordinate Fe2+ to limit its reactivity

Summary

Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells.

Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis.

Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4).

Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin.

To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron.

Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution.

These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance."

Cells use a little-known molecule to protect themselves from iron overload | MIT News | Massachusetts Institute of Technology "This discovery points toward new combination strategies against cancer, and may explain the iron buildup seen in disorders such as early-onset Parkinson’s disease."

Polyamines buffer labile iron to suppress ferroptosis (no public access)

Polyamines buffer labile iron to suppress ferroptosis (preprint, open access)

Graphical abstract

Fig. 1 CRISPR screen identifies modulators of polyamine sensitivity

Fig. 2 Polyamine depletion promotes ferroptosis

Fig 3 Polyamines act independently of canonical ferroptosis regulators

Fig 4 Polyamine deficiency increases redox-active iron

Fig 5 Genetically encoded sensor for redox-active iron

A new pill to limit appetite and reduce obesity or to maintain weight

This seems to be an interesting new drug!

"Early results for a pill which mimics some of the chemistry of exercise have been positive, announced the company making the pill, Enveda. The trial was conducted in 88 non-obese people, with no adverse effects and none of the side effects often seen in GLP-1s, such as nausea or vomiting.

The pill mimics the enzyme lactate phenylalanine to make people more sensitive to leptin — the hormone which limits appetite — thereby helping to maintain weight loss rather than yo-yoing. The upcoming phase II trial will involve people who have come off GLP-1s to see if the drug can help them to maintain their weight loss."

"Exceptional safety was observed across 88 healthy volunteers. Phase 2 plans to test whether ENV-308 can help people maintain their weight after stopping GLP-1s. 

• ENV-308 is the first drug in human trials designed to mimic Lac-Phe, a pseudo dipeptide hormone released by the body in response to high-intensity exercise. 
• In its first clinical trial, ENV-308 was extremely well tolerated across 88 healthy volunteers, including for gastrointestinal safety – the most common side effect that leads to people stopping GLP-1 medicines. 
• The trial showed ENV-308 reduced circulating leptin, an exploratory signal that the drug reaches biology relevant to metabolic disease. 
• In animal studies, ENV-308 preserved lean muscle during weight loss and prevented weight regain after weight-loss therapy was stopped. 

..."

Nature Briefing: Translational Research

Enveda Reports Positive Phase 1 Results for ENV-308, the First Pill Designed From the Chemistry of Exercise (original news release)

Source

Gut bacteria influence mice social behavior through smell

Amazing stuff! Why do humans use perfume and deodorants?

When one metabolite molecule regulates aggressiveness of individuals!

"In a new study, Northwestern University neurobiologists discovered that gut bacteria and the nose work together to shape social behavior in mice, including who fights and who backs down. Using a combination of genetic and behavioral experiments, the scientists found gut microbes produce a pungent odor that other animals can smell. When detected, these scents trigger aggression and shape social hierarchies. The discovery reveals a previously unknown way the microbiome influences social interactions. ...

"Over the past 20 years, there's been a growing realization that microbes in the gut have profound influences on behavior and physiology," ... "They produce bioactive chemicals that affect the function of many organ systems, including the immune system, and can even cross the blood-brain barrier to affect behavior. These chemicals can also affect social behaviors through the sense of smell. While species use microbiome-derived chemicals for social communication, our study is the first to uncover the underlying mechanism." ...

In the new study, ... team focused on trimethylamine (TMA), a molecule produced in the gut that smells like dead, rotten fish. When gut bacteria break down choline-rich foods, such as eggs and meat, they generate TMA as a byproduct. The body's liver then converts TMA into an odorless metabolite. But in adult male mice, testosterone suppresses the liver enzyme that typically neutralizes TMA, allowing it to accumulate in urine.

"It seemed like mice use TMA as a male-specific odor," ...

To better understand why adult male mice produce this odor, ... team imaged the olfactory bulb within the brain to see which neurons respond to TMA. They specifically focused on trace amine-associated receptors (TAARs), a small family of odor detectors that are especially sensitive to strong-smelling molecules. Among the 14 TAARs in mice, the team found that TAAR5 is the most sensitive receptor to TMA and plays a central role in detecting the odor. ...

From scent to social hierarchy

When mice detect this scent, it changes how they behave. Dominant animals initiate fights, while subordinate mice adopt defensive postures—patterns that quickly establish a social hierarchy. 

But when ... team disabled TAAR5 in mice, those distinctions blurred. Mice still interacted with one another, but their behavior became more evenly matched. Without this signal, it took longer for clear dominant-subordinate relationships to emerge. ..."

From the highlights and abstract:

"Highlights

• TAAR5 deletion alters aggression and social dominance in male mice

• The effect of TAAR5 on social behavior occurs via the main olfactory pathway

• Blocking production of the TAAR5 ligand TMA by gut microbes reduces aggression

• A microbiome-derived chemical cue shapes mammalian social behavior via olfaction

Summary

Many species use microbiome-derived metabolites as chemosensory cues, yet the chemicals involved and the sensory pathways that detect and process them remain poorly understood.

Trimethylamine (TMA) is a volatile metabolite that is produced by the gut microbiome and selectively accumulated in the urine of sexually mature male mice.

Here, we show that TMA regulates inter-male aggression and social dominance by activating trace amine-associated receptor 5 (TAAR5) in the main olfactory system.

In wild-type mice, early aggressive behavior during male-male encounters strongly predicts eventual social status: dominant males initiate more attacks, whereas subordinate males display more defensive behaviors.

Deletion of TAAR5 eliminated this asymmetry, with dominant and subordinate mice showing similar levels of aggressive and defensive behaviors.

Strikingly, restoring TAAR5 expression in olfactory sensory neurons (OSNs) rescued the behavioral asymmetry, indicating that this effect is mediated by the main olfactory system and arguing against contributions from proposed TAAR5 expression in the brain.

Finally, pharmacological suppression of microbial TMA production reduced inter-male aggression, and this effect was reversed by painting treated males with TMA, showing that microbiome-derived TMA is the key volatile ligand for TAAR5 in this context.

Taken together, our findings identify TMA as a critical olfactory cue that signals the presence of sexually mature males and facilitates social hierarchy formation. More broadly, our results demonstrate that a microbiome-derived metabolite can shape mammalian social interactions through the main olfactory system and uncover a previously unrecognized role for the TAAR family in regulating social behavior."

Gut bacteria may influence social behavior through smell

A microbiome-derived olfactory signal regulates inter-male aggression and social dominance in mice (open access)

Graphical abstract

Mouth microbiome linked to obesity and metabolic health

Amazing stuff!

"... But a new study published in Cell Reports suggests the mouth may be carrying its own metabolic fingerprint. In saliva samples from 628 adults, researchers at New York University Abu Dhabi found that people living with obesity host a distinct oral microbiome, one that differs not just in species, but in what those microbes are actively doing. ...

For the study participants with obesity, bacteria were more active in pathways linked to sugar fermentation and lactate production, while showing reduced capacity to generate certain essential nutrients. Across all participants, body mass index stood out as one of the strongest drivers of oral microbial variation, suggesting the microbiome of the mouth may reflect a broader metabolic state. These changes were not random, but instead pointed in a consistent metabolic direction. Species linked to inflammation and lactate production became more prominent, including proinflammatory Streptococcus parasanguinis and Actinomyces oris, along with the lactate-producing Oribacterium sinus, while others associated with nutrient synthesis receded. A shift that went deeper than simple taxonomy. ..."

From the highlights and abstract:

"Highlights

• Oral microbiome composition and functions differ significantly in obesity

• Obesity is linked to proinflammatory and lactate-producing oral bacteria

• Obese individuals show disrupted oral metabolism and altered energy balance

• Obesity-linked metabolites correlate with cardiometabolic disease markers

Summary

Obesity is a leading global health challenge and risk factor for cardiometabolic disorders, driven in part by industrialization and low-fiber, ultra-processed diets. While the gut microbiome has been implicated in obesity, the contribution of the oral microbiome—the body’s second largest microbial ecosystem—remains underexplored. We analyze a prospective cohort of 628 Emirati adults, including multi-omics profiling of 97 obese individuals and 95 matched controls, generating the most comprehensive oral microbiome analysis to date.

Obese participants show altered microbial diversity, composition, functions, and metabolites with enrichment of proinflammatory Streptococcus parasanguinis, Actinomyces oris, and lactate-producing Oribacterium sinus. Pathways for carbohydrate metabolism, histidine degradation, and obesogenic metabolites are upregulated, whereas B-vitamin and heme biosynthesis are depleted. Corresponding metabolites—including lactate, histidine derivatives, choline, uridine, and uracil—are elevated and correlate with obesity-linked cardiometabolic markers.

These findings reveal mechanistic oral microbiome-metabolite shifts, highlighting oral microbiome-host interactions as novel targets for obesity prevention and intervention."

Mouth microbiome linked to obesity and metabolic health

NYU Abu Dhabi Researchers Reveal an Association Between Mouth Bacteria and Obesity and Metabolic Health (original news release)

Integrative multi-omics analysis reveals oral microbiome-metabolome signatures of obesity (open access)

Graphical abstract

How food shortages reprogram immune system response

Amazing stuff!

It appears this article was not yet published in the Immunity journal as of now according to Google Scholar and the Immunity journal! The article below does not contain a link to the journal article.

Notice how ideology and demagoguery permeates this article by Cornell University! The use of the ideological term "food insecurity" in this context is foolish and wrong! There is a huge difference between a food scarcity and food insecurity!

"When food is scarce, stress hormones direct the immune system to operate in “low power” mode to preserve immune function while conserving energy ... This reconfiguration is crucial to combating infections amid food insecurity [???]. ...

The answer could help the 47 million Americans who are food insecure [???] and face the risk of infectious diseases every day. ...

The results ... found that mice on a calorie-restricted diet fought off infection as well as mice that were fully fed, but did so while using very little glucose. This was possible thanks to glucocorticoids, stress hormones known for their role in regulating blood glucose. The researchers determined that glucocorticoids acted like master conductors, reorganizing immune cells and their energy usage to provide a survival advantage. ..."

How food shortages reprogram immune system response | Cornell Chronicle

How do snakes go for many months without eating?

Amazing stuff!

"... The trick may be losing the genes that produce ghrelin, a key hormone that regulates appetite, digestion, and fat storage.

The team scanned the genomes of 112 species, seeking changes in the DNA that makes ghrelin, dubbed the “hunger hormone ” because it was once thought to be the key to obesity in humans.

In snakes, chameleons, and toadhead agamas, ghrelin genes were either missing or so warped by mutations they could no longer encode the hormone, the scientists found. When the researchers looked at MBOAT4, an enzyme that makes ghrelin function, they found that it too was lost in snakes, chameleons, and the agamas.

Losing ghrelin and MBOAT4 may have been part of how these ambush predators adapted to a boom-and-bust feeding schedule. Normally, ghrelin can help the body turn fat into energy when food is scarce. Without ghrelin and MBOAT4, the reptiles may be able to hold onto their energy reserves for longer, letting them persist in low power mode for months to a year between meals. ..."

ScienceAdviser

Gut molecule that blocks ‘hunger hormone' may spur new treatments for diabetes, anorexia (no public access)

Loss of ‘hunger hormone’ has made snakes masters of fasting (no public access)

How Exercise and physical fitness Slows Tumor Growth and progression at all stages of cancer

Good news! Cancer is history (soon)! A sedentary lifestyle and lack of physical fitness is good for cancer growth and progression!

"... In the study, ... team used metabolic tracers in mouse models of breast cancer and melanoma to learn how glucose—a nutrient that tumors use to fuel rapid cell division—is distributed when the body is active. The answer, they found, is that working muscles effectively outcompete tumors for the glucose supply. Because muscle contraction increases glucose uptake, exercise shifts metabolism, causing tumors to receive less of the fuel they need to grow. ..."

From the significance and abstract:

"Significance

It is well established from both preclinical and clinical studies that exercise protects against tumor growth and progression. However, the biomarkers of this beneficial effect are not well delineated. Here, we demonstrate using stable isotope tracer methodology and unbiased metabolomics analyses that aerobic exercise induces glucose repartitioning in rodents with breast cancer and melanoma. We further demonstrate that fitness—which can be measured along a continuum, beyond the binary “exercise/no exercise” paradigm that may not translate well to humans in practice—is a key predictor of tumor metabolism. These data highlight the importance of a nuanced, systemic view of the metabolic effects of exercise in cancer.

Abstract

Higher exercise capacity and regular exercise training improve cancer prognosis at all stages of disease. However, the metabolic adaptations to aerobic exercise training that mediate tumor–host interactions are poorly understood.

Here, we demonstrate that voluntary wheel running slows tumor growth and repartitions glucose uptake and oxidation to skeletal and cardiac muscle and away from breast and melanoma tumors in mice.

Further, prehabilitation induces repartitioning of glucose metabolism in obese mice: Uptake and oxidation of glucose are enhanced in skeletal and cardiac muscle, and reduced in tumors.

These increases in muscle glucose metabolism and reductions in tumor glucose metabolism, correlated with slower tumor progression.

Using [U-13C6] glucose infusion, we show that exercise increases the fractional contribution of glucose to oxidative metabolism in muscle while reducing it in tumors, suggesting that aerobic exercise shifts systemic glucose metabolism away from the tumor microenvironment and toward metabolically active tissues. Transcriptional analysis revealed downregulation of mTOR signaling in tumors from exercised mice.

Collectively, our findings suggest that voluntary exercise may suppress tumor progression by enhancing host tissue glucose oxidation and limiting tumor glucose availability, supporting a model in which exercise-induced metabolic competition constrains tumor energetics."

How Exercise Slows Tumor Growth | Internal Medicine

Precancer exercise capacity and metabolism during tumor development coordinate the skeletal muscle–tumor metabolic competition (no public access)

Metabolites in million-year-old fossils reveal animals’ lives in detail

Amazing stuff!

Notice this study also mentions warmer temperatures than today millions of years before humans released CO2!

"About 2.4 million years ago, a large, now-extinct elephant meandered along the grassy shores of Lake Malawi in East Africa. Today, scientists know it was a juvenile that munched wormwood bark and mulberry leaves—and may have been fighting an infection when it died.

In a study ... scientists report that fossil bones and teeth from that elephant and other fossil animals dating back millions of years ago contain metabolites, tiny byproducts of internal metabolic processes. These compounds can reveal hidden insights into past environments, including details such as soil acidity and ancient pathogens. The work highlights the promise of such work to provide a window into the past. ...

The study “inaugurates paleometabolomics”—as the field is known—“as a robust, biomolecular tool for extracting … data from millions-of-years-old fossils,” ..."

"For the first time, scientists have analyzed metabolism-related molecules from the fossilized bones of animals that lived 1.3 to 3 million years ago, revealing insights about both the animals and their environments.

The metabolic clues about the animals’ health and diets enabled researchers to paint a picture of their living conditions, including the temperature, soil, rainfall, and vegetation. Their findings, published in Nature, reveal warmer and wetter conditions across these environments compared to today.

Studying metabolites—the molecules produced and used in digestion and other chemical processes in the body—can provide information about health and disease, as well as external factors like diet and environmental exposures. While metabolomic research is increasingly used in studying human diseases and drugs, few scientists have explored its use in understanding the prehistoric world. Instead, they largely focus on DNA in fossils, which is primarily used for establishing genetic relationships. ..."

From the abstract:

"The science of metabolic profiling exploits chemical compound byproducts of metabolism called metabolites that explain internal biological functions, physiological health and disease, and provide evidence of external influences specific to an organism’s habitat.
Here we assess palaeometabolomes from fossilized mammalian hard tissues as a molecular ecological strategy to provide evidence of an ancient organism’s relationship with its environment.
From eastern, central and southern African Plio-Pleistocene localities of palaeoanthropological significance, we study six fossils from Olduvai Gorge, Tanzania, one from the Chiwondo Beds, Malawi, and one from Makapansgat, South Africa.
We perform endogeneity assessments by analysing palaeometabolomes of palaeosols and the effects of owl digestion on rodent bones to enable prudent ecological inferences.

Diagenesis is indicated by metabolites of collagenase-producing bacteria, whereas the preservation of peptides including those of collagen are identified by proteomics.

Endogenous metabolites document biological functions and exogenous metabolites render environmental details including soil characteristics and woody cover, and enable annual minimum and maximum rainfall and temperature reconstructions at Olduvai Gorge, supporting the freshwater woodland and grasslands of Olduvai Gorge Bed, and the dry woodlands and marsh of Olduvai Gorge Upper Bed II6.

All sites denote wetter and/or warmer conditions than today.

We infer that metabolites preserved in hard tissues derive from an extravasated vasculature serum filtrate that becomes entombed within developing mineralized matrices, and most probably survive palaeontological timeframes in the nanoscopic ‘pool’ of structural-bound water that occurs in hard tissue niches."

Chemicals in million-year-old fossils reveal animals’ lives in detail | Science | AAAS "Ancient meals and infections reconstructed from preserved metabolic markers"

Metabolic Analyses of Animal Fossils Helps Scientists Reconstruct Million-Year-Old Environments (original news release) "Thanks to molecules trapped in ancient animal bones, fossils tell stories about disease, diet, and climate"

Palaeometabolomes yield biological and ecological profiles at early human sites (no public access)

A polarized light image of fossilized antelope bone showing intact collagen (scale: 1 mm across)

Key enzyme controls both weight gain and cholesterol levels in animal models

Good news!

"... Nitric oxide is a gas molecule with pleiotropic actions in the body. These effects of nitric oxide are carried out through its binding to proteins. Too much or too little nitric oxide binding (to key proteins) causes disease.

In a study ... a research team ... discovered a novel enzyme (SCoR2) that removes nitric oxide from proteins controlling fat build up. Removal of nitric oxide turned on fat synthesis, establishing that SCoR2 is needed to make fat.

The team then inhibited SCoR2 genetically and by developing a drug. They found that blocking this nitric oxide-removing enzyme prevented weight gain and liver injury in mouse models. The same drug also lowered bad cholesterol.

"We have a new class of drug that prevents weight gain and lowers cholesterol—a potential therapy for obesity and cardiovascular disease, with additional hepatic benefits," ..."

"... 

• Cleveland research team has discovered a new enzyme that is required to make fat.
• Blocking the enzyme prevented weight gain and lowered cholesterol.
• A three-in-one drug is being developed to treat obesity, fatty liver disease, and cardiovascular disease.

..."

From the editor's summary and abstract:

"Editor’s summary

Hypertrophy of white adipose tissue due to triglyceride storage and steatosis in the liver due to excessive de novo lipogenesis have detrimental metabolic effects. Venetos et al. found that these processes were stimulated by the enzymatic removal of S-nitrosyl (SNO) groups from distinct protein targets in white adipose tissue and liver by the denitrosylase SCoR2.
Mice deficient in SCoR2 or given a SCoR2 inhibitor were metabolically protected from obesogenic diets because of increased fatty acid oxidation in the liver and reduced adipose tissue expansion.
Moreover, SCoR2 mRNA or protein abundance correlated with obesity, adipocyte surface area, or steatotic liver disease in patients. Thus, because SCoR2 activity skews global lipid metabolism toward storage and synthesis, this denitrosylase could be targeted to treat both obesity and hepatic steatosis. ...

Abstract

Lipid homeostasis is subject to control by posttranslational modification machinery, such as sirtuin deacetylases that reverse coenzyme A (CoA)–dependent acetylation.

Here, we showed that a mammalian denitrosylase (SCoR2), which counteracts CoA-dependent S-nitrosylation, promoted both fat storage and lipogenesis to impair metabolic health.
In mice, SCoR2 protein abundance correlated with body mass, and deleting or pharmacologically inhibiting SCoR2 prevented both diet-induced obesity and metabolic dysfunction–associated steatotic liver disease (MASLD).
Loss of SCoR2 in adipocytes promoted the S-nitrosylation of the actin cytoskeletal regulator myosin 9, which inhibited the activity of the lipogenesis-promoting transcription factors PPARγ, SREBP1, and CEBPα to prevent fat storage.
In hepatocytes, inhibition of SCoR2-mediated denitrosylation of lipogenic enzymes reduced fat synthesis and induced fat oxidation.
In humans, an obesity-linked polymorphism was associated with increased SCoR2 mRNA expression, and in patient adipose and liver tissues, SCoR2 protein or mRNA abundance directly correlated with adipocyte size or MASLD.
These results indicate that SCoR2 regulates nutrient metabolism, similar to sirtuins, and is a potential drug target for obesity and MASLD."

Key enzyme controls both weight gain and cholesterol levels in animal models

Cleveland Researchers Discover Enzyme That Controls Both Weight Gain and Cholesterol Levels in Animal Models (original news release)

The protein denitrosylase SCoR2 regulates lipogenesis and fat storage (no public access)

Gut microbes use common nutrient choline to fight type 2 diabetes

Good news! Is a choline dietary supplement a good idea?

"... Earlier this year, for example, it was found that an antibiotic primarily used in veterinary medicine was able to convince the microbes in mouse guts to produce colonic acid, a life-extending compound.

Now, a team led by a researcher ... has figured out another powerful way our gut microbes can help us out – this time by tamping down inflammation caused by a fatty diet, keeping our insulin response in check and, in turn, warding off diabetes. ...

The researchers found that one of the chemicals involved in this cascade of negative effects is the immune-system protein IRAK4, which triggers inflammation in the presence of a high-fat diet as a sort of alarm bell. When that protein is expressed for an extended period of time, it leads to insulin resistance and diabetes. ...

Using mice, human cell models, and molecular target-screening, the scientists found that when the nutrient choline hits the gut, microbes convert it into a metabolite called trimethylamine (TMA). TMA, in turn, binds to IRAK4, blocks its activity, reduces inflammation, and restores insulin sensitivity. ..."

"An international research team ... has uncovered a surprising ally in the fight against insulin resistance and type 2 diabetes: a microbial metabolite called trimethylamine (TMA). ... the study reveals that TMA, produced by gut bacteria from dietary choline can block a key immune pathway and improve blood sugar control. ..."

From the abstract:

"The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered.
Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock.
Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets.

Remarkably, our results suggest that TMA—unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease—improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial–mammalian chemical crosstalk."

Gut microbes use common nutrient to fight type 2 diabetes

Microbial molecule offers new hope for diabetes (original news release)

Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control (open access)

Fig. 1: Choline supplementation improves glucose homoeostasis and inflammation after 5 months of HFD [high fat diet]. 

A tiny protein complex controls fat cell size and lipid storage

Good news!

"Scientists have made a major breakthrough in understanding how fat cells grow in size, in response to accommodating larger droplets of fat. The findings unlock a new path in tackling obesity, by reducing the amount of fat our cells can store away. ...

Earlier ... research had identified a protein known as seipin that was critical for healthy lipid storage across organisms, including humans. But how seipin was facilitating this remained unknown, and despite some studies naming another protein – adipogenin – in the process, scientists didn't know how it was involved.

Using cryo-electron microscopy, the researchers found that adipogenin was more than a bystander in the process, reinforcing seipin's structural integrity to enhance its ability to form and deliver lipid droplets to cells. The result is adipocytes accommodating larger lipid droplets – and increasing the size of these fat cells. ..."

From the abstract of the Perspective:

"Obesity is characterized by the accumulation of triacylglycerols in lipid droplets of adipocytes (fat cells) and the expansion of adipose tissue. Adipocytes arise from stem cells through adipogenesis, a process driven by several transcription factors ... Li et al. (3) identify adipogenin as a molecular switch that shifts the emphasis from generating new lipid droplets to expanding existing ones during adipogenesis."

From the editor's summary and abstract:

"Editor’s summary

Fat storage in the body relies on specialized structures called lipid droplets (LDs). Li et al. identified the microprotein adipogenin as a regulator of adipocyte LD size ... Adipogenin interacts with the membrane protein seipin and stabilizes the assembly of seipin dodecamers by bridging adjacent subunits. Functionally, seipin-adipogenin complexes promote the formation of fewer but larger LDs. In mice, adipocyte-specific adipogenin overexpression results in increased fat mass and larger LDs, whereas adipogenin deletion reduces fat accumulation and LD size, particularly in brown adipose tissue. Thus, adipogenin represents a modulator of adipocyte lipid storage that acts through a structural and functional partnership with seipin. ... 

Abstract

INTRODUCTION

Adipogenin (Adig) is an 80–amino acid microprotein that is highly expressed in adipose tissues and steatotic liver. A previous genome-wide association study suggested that human ADIG is associated with blood leptin levels, highlighting its importance in energy metabolism. At the molecular level, Adig’s function is largely unknown: No interacting proteins have been identified. ...

RATIONALE

Microproteins typically exert their functions by binding to larger proteins and regulating their activities. We pulled down Adig from adipocytes and identified its interacting proteins by mass spectrometry. Upon the identification of a seipin-Adig complex, we resolved its structure using cryo–electron microscopy (cryo-EM), enabling us to determine Adig’s effect on seipin configuration at an atomic scale. Because seipin plays a vital role in lipid droplet (LD) formation and growth, we explored the function of the seipin-Adig complex in these processes. Moreover, we generated adipocyte-specific Adig overexpression and deletion mice to investigate Adig’s effect on adipose tissue expansion and lipid metabolism in vivo.

RESULTS

We found that Adig is a highly conserved protein with a single transmembrane (TM) segment that localizes to the endoplasmic reticulum (ER). Notably, Adig and seipin can form a complex and stabilize each other.

Cryo-EM analysis revealed two distinct oligomers: an undecameric seipin-alone complex at ~3.2-Å overall resolution and a dodecameric seipin-Adig complex at ~3.0-Å overall resolution.

In the seipin-Adig complex map, extra densities, corresponding to seipin and Adig TM domains, were observed. Multiple approaches, including high-resolution imaging, gel filtration, and molecular dynamics simulations, revealed that Adig could facilitate the assembly of dodecameric seipin complexes. Seipin complexes with varying Adig contents modulated LD formation and growth. The presence of the seipin-Adig complex altered triacylglycerol (TAG) flux in the ER, leading to the formation of fewer, but larger, LDs.

Additionally, the ER-to-LD trafficking of select lipid-synthesizing enzymes was accelerated in Adig-expressing cells.

In mice, Adig overexpression in adipocytes promoted LD enlargement and adipose tissue expansion, whereas Adig deletion decreased the amount of the seipin complexes in adipocytes and impaired TAG accumulation in brown adipose tissues.

CONCLUSION

In this study, we demonstrate that Adig complexes with seipin, forming a previously unrecognized dodecameric seipin complex. Furthermore, Adig stabilizes and promotes the assembly of this complex, thereby supporting LD growth in cells. In mice, modulating the expression of seipin-Adig complexes in adipose tissues by Adig overexpression or deletion substantially affects LD formation and expansion as well as lipid absorption by adipose tissues. This study reveals Adig as a key cofactor that modulates seipin function and fat storage in adipose tissue. We conclude that the oligomerization and function of seipin complexes can be modulated by Adig expression."

A key protein controls fat cell size and lipid storage

Seipin-adipogenin controls lipid storage in fat cells (Perspective, no public access) "A protein complex promotes the expansion of lipid droplets during the formation of mature adipocytes"

Microprotein plays vital role in fat accumulation (original news release) "Findings from UTSW researchers, colleagues could lead to new treatments to improve metabolic health and reduce risks of obesity, diabetes"

Adipogenin promotes the development of lipid droplets by binding a dodecameric seipin complex (no public access)

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex (preprint, open access, but seems to be dated and does not match the journal article)

Seipin-Adig complex promotes the development of lipid droplets.

Reprogrammed Human Stomach Organoids Secrete Insulin

Good news!

"... Now, researchers ... engineered human stomach organoids to secrete insulin. Transplanting these into diabetic mice reduced hyperglycemia.2 Their findings, published today in Stem Cell Reports, could help develop technologies to engineer a person’s own insulin-secreting cells for diabetes treatment. ..."

From the highlights and abstract:

"Highlights

• Engrafted human gastric organoids (hGOs) model human stomach in vivo

• NPM factor induction converts hGOs into insulin+ β-like cells in vitro and in vivo

• In situ gastric reprogramming offers potential for autologous diabetes cell therapy

Summary

Insulin-dependent diabetes could be treated by supplying patients with primary pancreatic islets or other types of insulin-secreting cells. Functional insulin-secreting cells can be induced in situ from the murine stomach using defined genetic factors, offering a promising method to directly produce autologous insulin-secreting cells.

Here, we modeled whether such gastric insulin-secreting (GINS) cells could be generated in vivo from human stomach tissues. We produced human gastric organoids (hGOs) from human embryonic stem cells engineered with inducible expression of reprogramming factors.

The hGOs were stably transplanted for 6 months and showed robust cytodifferentiation resembling the human stomach in structure and cellular composition.

Upon hGO maturation in vivo, we activated the reprogramming factors and observed the formation of insulin+ cells, which secreted insulin into the circulation and ameliorated experimental diabetes.

Our modeling indicates that GINS cells can be induced from human stomach tissues in vivo, warranting further therapeutic development for this technology."

Reprogrammed Human Stomach Organoids Secrete Insulin | The Scientist

Modeling in vivo induction of gastric insulin-secreting cells using transplanted human stomach organoids

Figure 1 Generation of hGOs from hESCs with inducible expression of NPM factors

A fat-storage mystery solved? May improve treatment of obesity.

Amazing stuff! Good news!

"The story scientists have long told about how fat cells function contains a puzzling paradox. An enzyme called hormone-sensitive lipase (HSL) is known to chop up fat stored in these cells, called adipocytes, to release energy. But people who can’t make HSL because of a condition called lipodystrophy don’t store excess fat and aren’t obese—in fact, they struggle to maintain adequate fat levels. HSL, it turns out,  has an unexpected second role. Rather than operating only as an enzyme in the cytoplasm as was originally thought, it also enters the nucleus of an adipocyte and controls its gene activity to maintain the health and structure of fat tissue.

Researchers found that silencing the gene for HSL in cultured human fat cells turned up the genes that drive cells’ tiny energy generators, called mitochondria; it also dialed down genes responsible for building the protein framework that gives fat tissue its structure. The cells also started to look more like fat-burning “beige” adipocytes rather than fat-storing white adipocytes, indicating they had more mitochondria. In experiments with genetically modified mice, the team confirmed that the ability to maintain normal fat stores depends on levels of nuclear, not cytoplasmic HSL.

They also found that obese lab mice tended to have excess HSL in the nucleus of their fat cells, suggesting the protein’s overactivity there could alter fat tissue structure and contribute to obesity. The findings could inform future therapies that focus on restoring fat cell function instead of just shrinking fat stores."

From the highlights and abstract:

"Highlights

• Hormone-sensitive lipase is localized within the nuclei of adipocytes

• In vivo, nuclear HSL levels regulate adipose tissue mass

• In vitro, nuclear HSL controls mitochondria and extracellular matrix gene expression

• HSL nuclear level is regulated by TGF-β and PKA signaling pathways

Summary

In adipocytes, hormone-sensitive lipase (HSL) plays a key role in hydrolyzing triacylglycerols that are stored in lipid droplets. Contrary to the expected phenotype, HSL-deficient mice and humans exhibit lipodystrophy.

Here, we show that HSL is also present in the adipocyte nucleus. Mouse models with different HSL subcellular localizations reveal that nuclear HSL is essential for the maintenance of adipose tissue.

Gene silencing in human adipocytes shows that HSL, independently of its enzymatic activity, exerts opposing effects on mitochondrial oxidative phosphorylation and the extracellular matrix.

Mechanistically, we found that HSL accumulates in the nucleus by interacting with the transforming growth factor β (TGF-β) signaling mediator, mothers against decapentaplegic homolog 3 (SMAD3).

Conversely, HSL phosphorylation induces nuclear export. In vivo, HSL accumulates in the nucleus of adipocytes during high-fat feeding with the converse effect during fasting.

Together, our data show that as both a cytosolic enzyme and a nuclear factor, HSL plays a pivotal role in adipocyte biology and adipose tissue maintenance."

ScienceAdviser

Fat-chomping enzyme that ‘moonlights’ as gene regulator could point to obesity treatments "Hormone-sensitive lipase works in the nucleus to keep fat cells healthy, new study suggests"

Nuclear hormone-sensitive lipase regulates adipose tissue mass and adipocyte metabolism (open access)

Graphical abstract

Exercise metabolite Lac-Phe curbs appetite naturally in mice, humans, and racehorses

Good news!

"Researchers led by scientists at Baylor College of Medicine (BCM) have unraveled just how an exercise-induced signaling metabolite, N-lactoyl-phenylalanine (Lac-Phe), travels a unique pathway to the brain and impacts the activity of one, and then two different neurons. It triggers a chain of events that ultimately suppresses appetite ..."

"... The researchers previously discovered that Lac-Phe is the most increased metabolite – a product of the body’s metabolism – in blood after intense exercise, not just in mice but also in humans and racehorses. The team’s previous work showed that giving Lac-Phe to obese mice reduced how much they ate and helped them lose weight without negative side effects. But until now, scientists didn’t fully understand how Lac-Phe works to suppress appetite. ...

The researchers studied two types of brain cells in mice. One type was AgRP neurons, which stimulate hunger and are in the arcuate nucleus of the hypothalamus. The other type was PVH neurons in the paraventricular nucleus of the hypothalamus. These neurons help suppress hunger.

AgRP and PVH neurons work together. Normally, AgRP neurons send signals that inhibit PVH neurons, making you feel hungry. But when AgRP neurons are turned off, PVH neurons become more active, reducing appetite.

He lab members and colleagues discovered that Lac-Phe directly inhibits AgRP neurons, which in turn activates PVH neurons. This chain of events resulted in mice eating less. The animals’ behavior remained normal, suggesting that Lac-Phe doesn’t cause unpleasant side effects. ..."

From the abstract:

"N-Lactoyl-phenylalanine (Lac-Phe) is a lactate-derived circulating metabolite that reduces feeding and obesity, but the molecular mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown.

Here we show that Lac-Phe directly inhibits hypothalamic neurons that express Agouti-related protein (AgRP), resulting in an indirect activation of anorexigenic neurons in the paraventricular nucleus of the hypothalamus (PVH).

Both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. 

Lac-Phe-mediated inhibition of AgRP neurons occurs through activation of the ATP-sensitive potassium (KATP) channel, whereas inhibition of the KATP channel blunts the effects of Lac-Phe to suppress feeding.

Together, these results reveal the molecular and neurobiological mechanisms by which Lac-Phe mediates metabolic improvements and suggest this exercise-induced metabolite might have therapeutic benefits in various human diseases."

Exercise metabolite Lac-Phe curbs appetite naturally

New study sheds light on how exercise helps lose weight (original news release)

Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice (no public access)

Unlocking the genetic ‘control switches’ of hibernation

Amazing stuff! When can I go into hibernation to wake up perhaps in the next century? 😴

"New research has identified specific regions of DNA that regulate hibernation by tweaking metabolism. The findings could offer pathways to new treatments for metabolic disorders like type 2 diabetes in humans.

When hibernating animals wake, they reverse dangerous health changes similar to those seen in type 2 diabetes, muscle atrophy, Alzheimer’s disease and stroke. ...

Ferris is co-author of 2 new studies which pinpointed that DNA regions near a gene cluster called the “fat mass and obesity (FTO) locus” play a crucial role in the ability to hibernate. While the FTO locus also appears in humans, hibernating animals use it in a different, and potentially more advantageous way. ...

The hibernator-specific DNA regions (located close to the FTO locus) weren’t genes but DNA sequences called “cis–regulatory elements” (CREs) which contact nearby genes to either turn up or down their expression, ... The researchers found the CREs regulated the activity of neighbouring genes, including those involved in metabolism. ..."

From the editor's summary and abstract:

"Editor’s summary

Metabolic regulation is fundamental to many aspects of health and disease. Two companion papers investigated the genetic bases of mammalian metabolic control by studying the genetic changes associated with hibernation. Ferris et al. performed a comparative analysis of gene expression and chromatin dynamics in a non hibernating mouse and a hibernating squirrel, focusing on the hypothalamus, a brain area involved in metabolic adaptations. They identified a convergent set of cis-regulatory elements (CREs) associated with the adoption of a hibernating lifestyle. Steinwand et al. performed targeted deletion of some of these CREs, determining how these specific alterations translated into distinct metabolic and behavioral phenotypes. These studies suggest that CREs might also play a role in regulating human metabolism. ...

Abstract

Cis-regulatory elements (CREs) drive phenotypic diversity, yet how CREs are causally linked to function remains largely unclear.

Our study elucidates functions for conserved cis elements associated with the evolution of mammalian hibernation and metabolic flexibility.

Genomic analyses revealed topologically associated domains (TADs) enriched for convergent changes in hibernators, including the Fat Mass & Obesity (Fto) locus. In this TAD, we uncovered genetic circuits for metabolic responses and hibernation-linked cis elements forming regulatory contacts with neighboring genes.

Deletions of individual cis elements in mice differentially altered Fto, Irx3, and Irx5 expression, reshaping downstream gene expression programs and affecting metabolism, torpor, obesogenesis, and foraging in distinct ways.

Our findings show how convergent evolution in hibernators pinpoints functional genetic mechanisms of metabolic control, with multiple effects encoded in single CREs."

Unlocking the genetic ‘control switches’ of hibernation

Hibernator “Superpowers” May Lie Hidden in Human DNA (original news release)

Conserved noncoding cis elements associated with hibernation modulate metabolic and behavioral adaptations in mice (no public access)

Conserved Noncoding Cis-Elements Associated with Hibernation Modulate Metabolic and Behavioral Adaptations in Mice (preprint, open access)

Fig. 1 Convergent genomic changes in hibernators identify Fto-Irx TAD cis-elements for functional analysis in knockout mice.

The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine

Amazing stuff! A 30 year old mystery resolved about an important micronutrient. And it's an oncogene.

"... First discovered in the 1970s, queuosine – pronounced “cue-o-scene” – is a vitamin-like micronutrient that human bodies are incapable of making ourselves. Instead, the micronutrient enters the body from food and our gut bacteria. ...

In their research, the team were able to identify SLC35F as the specific gene responsible for transporting the micronutrient around the body that helps translate genetic codes into proteins. ...

The gene has been maintained across millions of years of evolution, being present in both simple, single-cell organisms to modern day humans, indicating its functional importance for life.  ..."

"An international team of scientists ... has cracked a decades-old mystery in human biology: how our bodies absorb a micronutrient that we rely on for everything from healthy brain function to cancer defense. 

Queuosine – pronounced “cue-o-scene” – is a vitamin-like micronutrient that we can't make ourselves but can only get from food and our gut bacteria. It’s vital to our health, yet its importance went unnoticed for decades.  ..."

From the significance and abstract:

"Significance

The identification of SLC35F2 as the eukaryotic transporter of queuine and queuosine is key to understanding how these micronutrients are salvaged from the human gut and distributed to different body tissues. Queuosine modification of transfer RNAs (tRNAs) enhances the accuracy and efficiency of codon–anticodon pairing and regulates a range of biological and pathophysiological states, including oxidative stress responses, cancer, learning, memory, and gut homeostasis.

Abstract

The nucleobase queuine (q) and its nucleoside queuosine (Q) are micronutrients derived from bacteria that are acquired from the gut microbiome and/or diet in humans. Following cellular uptake, Q is incorporated at the wobble base (position 34) of tRNAs that decode histidine, tyrosine, aspartate, and asparagine codons, which is important for efficient translation.

Early studies suggested that cytosolic uptake of queuine is mediated by a selective transporter that is regulated by mitogenic signals, but the identity of this transporter has remained elusive.

Here, through a cross-species bioinformatic search and genetic validation, we have identified the solute carrier family member SLC35F2 as a unique transporter for both queuine and queuosine in Schizosaccharomyces pombe and Trypanosoma brucei.

Furthermore, gene disruption in human HeLa cells revealed that SLC35F2 is the sole transporter for queuosine (Km 174 nM) and a high-affinity transporter for the queuine nucleobase (Km 67 nM), with the additional presence of second low-affinity queuine transporter (Km 259 nM).

Ectopic expression of labeled SLC35F2 reveals localization to the cell membrane and Golgi apparatus via immunofluorescence. Competition uptake studies show that SLC35F2 is not a general transporter for other canonical ribonucleobases or ribonucleosides but selectively imports q and Q.

The identification of SLC35F2, an oncogene, as the transporter of both q and Q advances our understanding of how intracellular levels of queuine and queuosine are regulated and how their deficiency contributes to a variety of pathophysiological conditions, including neurological disorders and cancer."

Solving a 30-year old micronutrient mystery vital to health

UF, Trinity College team cracks micronutrient mystery that could be key to brain health, cancer defense (original news release)

The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine (no public access)

The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine (preprint, open access)

Fig. 1 Transport of q and Q into eukaryotes and subsequent intracellular utilization.

Fig. 2 The SLC35F transporter family is functionally diverse.

Neurons use built-in ‘backup batteries’ that fuel the brain under stress with glycogen

Amazing stuff!

"... describe how neurons store their own glycogen, a form of sugar that helps neurons stay resilient when their main energy sources falter. 

The findings illustrate how neuron cells can adapt their metabolism, researchers say, and could shape new treatments for neurological conditions like stroke, neurodegeneration, and epilepsy, all disorders in which energy failure plays a role. ...

A breakthrough came when researchers discovered the enzyme PYGL-1, the worm’s version of the human glycogen phosphorylase enzyme that converts glycogen into fuel for neurons. When researchers removed PYGL-1, the worm neurons could no longer ramp up energy during low-oxygen stress conditions; when the enzyme was specifically restored in neurons, that failure was reversed.

“We discovered that neurons use two different strategies to adapt to energy stress: one that’s glycogen-dependent, and one that isn’t,”  ... “The glycogen-dependent pathway is particularly critical when the mitochondria — one of the cell’s primary energy producers — aren’t functioning well. In those situations, glycogen serves as a backup system to provide energy via glycolysis.” ..."

From the significance and abstract:

"Significance

It has long been assumed that glycogen in the brain is primarily a glial energy reserve, with limited direct relevance to neurons. Yet, recent studies have demonstrated a role for glycogen in neuronal function. Here, we extend these findings, demonstrating that neurons directly metabolize glycogen to support glycolysis in vivo. Using a metabolic biosensor in Caenorhabditis elegans, we uncover a neuron-intrinsic, glycogen-dependent glycolytic plasticity that is specifically activated during hypoxia and mitochondrial dysfunction. This direct neuronal use of glycogen is essential for sustaining synaptic function, revealing an unexpected and critical role for glycogen in neuronal energy metabolism.

Abstract

Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well understood.

We established a system in Caenorhabditis elegans to dynamically probe glycolytic states in single cells of living animals via the use of the glycolytic sensor HYlight and determined that neurons can dynamically regulate glycolysis in response to activity or transient hypoxia.

We performed an RNAi screen and identified that PYGL-1, an ortholog of the human glycogen phosphorylase, is required in neurons for glycolytic plasticity.

We determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity.

We uncover that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mutants for mitochondrial function. We find that the loss of GDGP impairs glycolytic plasticity and is associated with defects in synaptic vesicle recycling during hypoxia. Together, our study reveals that, in vivo, neurons can directly use glycogen as a fuel source to sustain glycolytic plasticity and synaptic function."

Neurons use built-in ‘backup batteries’ that fuel the brain under stress | Yale News "A new Yale study reveals that neurons store their own sugar reserves that kick in to keep the brain functioning during metabolic stress."

Glycogen supports glycolytic plasticity in neurons (open access)

Fig. 4 pygl-1/Glycogen phosphorylase is required for glycolytic plasticity and synaptic vesicle recycling during mitochondrial impairment.