“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver. Other studies have found that it acts through the gut,” said corresponding author Dr. Makoto Fukuda, associate professor of pediatrics — nutrition at Baylor. “We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism. We investigated whether and how the brain contributes to the anti-diabetic effects of metformin.”

Rap1 Protein and the Hypothalamus

The researchers focused on a small protein called Rap1, located in a brain region known as the ventromedial hypothalamus (VMH). They found that metformin’s ability to reduce blood sugar at clinically relevant doses relies on suppressing Rap1 activity in this specific area of the brain.

To test this idea, the Fukuda lab used genetically engineered mice that lacked Rap1 in the VMH. These mice were placed on a high-fat diet to model type 2 diabetes. When treated with low doses of metformin, their blood sugar levels did not improve. In contrast, other diabetes treatments such as insulin and GLP-1 agonists remained effective.

Direct Brain Effects of Metformin

To further confirm the brain’s role, researchers delivered very small amounts of metformin directly into the brains of diabetic mice. Even at doses thousands of times lower than those typically taken orally, the treatment led to a marked reduction in blood sugar levels.

“We also investigated which cells in the VMH were involved in mediating metformin’s effects,” Fukuda said. “We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they’re directly involved in the drug’s action.”

Neuron Activation and Blood Sugar Control

Using brain tissue samples, the team measured the electrical activity of these neurons. Metformin increased activity in most of them, but only when Rap1 was present. In mice that lacked Rap1 in these neurons, the drug had no effect, demonstrating that Rap1 is required for metformin to activate these brain cells and regulate blood sugar.

“This discovery changes how we think about metformin,” Fukuda said. “It’s not just working in the liver or the gut, it’s also acting in the brain. We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels.”

Implications for Diabetes Treatment and Brain Health

Although most diabetes medications do not target the brain, this research shows that metformin has been influencing brain pathways all along. “These findings open the door to developing new diabetes treatments that directly target this pathway in the brain,” Fukuda said. “In addition, metformin is known for other health benefits, such as slowing brain aging. We plan to investigate whether this same brain Rap1 signaling is responsible for other well-documented effects of the drug on the brain.”

Other contributors to this work include Hsiao-Yun Lin, Weisheng Lu, Yanlin He, Yukiko Fu, Kentaro Kaneko, Peimeng Huang, Ana B De la Puente-Gomez, Chunmei Wang, Yongjie Yang, Feng Li and Yong Xu. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Louisiana State University, Nagoya University — Japan and Meiji University — Japan.

This work was supported by grants from: National Institutes of Health (R01DK136627, R01DK121970, R01DK093587, R01DK101379, P30-DK079638, R01DK104901, R01DK126655), USDA/ARS (6250-51000-055), American Heart Association (14BGIA20460080, 15POST22500012) and American Diabetes Association (1-17-PDF-138). Further support was provided by the Uehara Memorial Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology and the NMR and Drug Metabolism Core at Baylor College of Medicine.

What Makes Gamma Cassiopeiae So Unusual

γ Cassiopeiae was the first star classified as a Be-type star, identified in 1866 by Italian astronomer Angelo Secchi. These massive stars spin rapidly and regularly eject material into space. That material forms a disc around the star, which can be detected through specific features in its optical spectrum.

In 1976, scientists realized that γ Cas emits X-rays about forty times stronger than similar stars. The plasma responsible reaches temperatures above 100 million degrees and changes rapidly. Over the following two decades, space observatories found around twenty stars with similar behavior, now known as ‘γ Cas analogues’. Astronomers at University of Liège played a major role in identifying more than half of these objects.

Competing Theories for the X-Ray Emission

“Several scenarios had been proposed to explain this emission,” explains Yaël Nazé, an astronomer at ULiège. “One of them involved local magnetic reconnection between the surface of the Be star and its disc. Others suggested X-rays to be linked to a companion, whether a star stripped of its outer layers, a neutron star, or an accreting white dwarf.”

Researchers had already ruled out stripped stars and neutron stars because observations did not match theoretical predictions. That left two possibilities: magnetic activity near the star or a nearby white dwarf pulling in material. Until recently, there was no clear way to distinguish between them.

XRISM Data Tracks the Source of the X-Rays

To resolve the mystery, the team carried out a series of observations using Resolve, a high-precision microcalorimeter on board XRISM that is transforming high-energy astrophysics. Data were collected in December 2024, February 2025, and June 2025, covering the full 203-day orbit of the system.

“The spectra revealed that the signatures of the high-temperature plasma change velocity between the three observations, following the orbital motion of the white dwarf rather than that of the Be star,” the researcher continues. “This shift was measured with high statistical reliability. It is, in fact, the first direct evidence the the ultra-hot plasma responsible for the X-rays is associated with the compact companion, and not with the Be star itself.”

Evidence for a Magnetic White Dwarf

The measurements also provide insight into the nature of the white dwarf. The spectral features have a moderate width (of the order of 200 km/s), which rules out a non-magnetic white dwarf. In that scenario, material would fall inward through rapidly rotating inner regions of the disc, producing much broader signals. Instead, the results indicate a magnetic white dwarf, where the disc is cut off and the magnetic field directs incoming material toward its poles (see figure).

A New Class of Binary Stars Confirmed

These findings show that γ Cas and similar stars belong to a class of Be + white dwarf binary systems that had long been predicted but never clearly observed. Researchers at ULiège also identified two key traits of this group. It mainly involves massive Be stars and represents about 10% of them. However, theoretical models had expected a larger population and suggested a stronger connection with lower-mass Be stars.

“This discrepancy suggests a revision of binary evolution models, particularly regarding the efficiency of mass transfer between components — a conclusion that aligns with that of several recent independent studies. Solving this mystery therefore opens up new avenues of research for the years to come! Understanding the evolution of binary systems is crucial for comprehending, for example, gravitational waves, as it is indeed massive binaries that emit them at the end of their lives,” concluded Yaël Nazé.

The findings, published in Monthly Notices of the Royal Astronomical Society, echo the kind of mission imagined in the Hollywood film Project Hail Mary. In that story, Ryan Gosling’s character travels to a distant star system in search of a way to save Earth, encountering alien life along the way, including a being named Rocky and fictional microorganisms like Astrophage and Taumoeba.

Habitable Zone Planets and Liquid Water Potential

Professor Lisa Kaltenegger, director of the Carl Sagan Institute at Cornell University, led the research alongside a team of undergraduate students. They analyzed new data from the European Space Agency’s Gaia mission and the NASA Exoplanet Archive to identify planets located in the “habitable zone.”

This region around a star is not too hot and not too cold, making it more likely that liquid water could exist on a planet’s surface. Since water is essential for life as we know it, planets in this zone are considered the best candidates.

The study, titled ‘Probing the limits of habitability: a catalogue of rocky exoplanets in the habitable zone’, also highlights planets that receive levels of stellar energy similar to Earth.

“As Project Hail Mary so beautifully illustrates, life might be much more versatile than we currently imagine, so figuring out which of the 6,000 known exoplanets would be most likely to host extraterrestrials such as Astrophage and Taumoeba — or Rocky — could prove critical, and not just to Ryan Gosling,” Professor Kaltenegger said.

“Our paper reveals where you should travel to find life if we ever built a ‘Hail Mary’ spacecraft.”

45 Rocky Worlds Identified as Top Targets

The team identified 45 rocky planets within the habitable zone that could potentially support life. They also highlighted an additional 24 planets within a more restrictive 3D habitable zone, based on tighter assumptions about how much heat a planet can tolerate before becoming uninhabitable.

Among these are well-known exoplanets such as Proxima Centauri b, TRAPPIST-1f, and Kepler 186f, along with lesser-known candidates like TOI-715 b.

Some of the most intriguing targets include the TRAPPIST-1 system planets d, e, f, and g, located about 40 light-years from Earth, as well as LHS 1140 b, which lies 48 light-years away. Whether these worlds can sustain liquid water depends partly on their ability to maintain an atmosphere.

Earth-Like Energy and Promising Nearby Worlds

Several planets receive levels of starlight similar to what Earth gets from the Sun. These include the transiting planets TRAPPIST-1 e, TOI-715 b, Kepler-1652 b, Kepler-442 b, and Kepler-1544 b, along with planets such as Proxima Centauri b, GJ 1061 d, GJ 1002 b, and Wolf 1069 b, which are detected through the motion they induce in their host stars.

Researchers also selected planets located near the inner and outer edges of the habitable zone to better understand where the limits of habitability lie. While the concept of the habitable zone has been studied since the 1970s, new observations could refine or even reshape current theories, Professor Kaltenegger explained.

Testing the Limits of Planetary Habitability

Some exoplanets follow highly elliptical orbits, meaning the amount of heat they receive from their star changes significantly over time. Studying these worlds could reveal whether a planet must remain continuously within the habitable zone or if it can move in and out while still maintaining conditions suitable for life.

Planets such as K2-239 d, TOI-700e, and K2-3d, along with Wolf 1061c and GJ 1061c, can help scientists study the inner boundary of habitability. Meanwhile, TRAPPIST-1g, Kepler-441b, and GJ 102 offer insight into the colder outer edge of the habitable zone.

“While it’s hard to say what makes something more likely to have life, identifying where to look is the first key step — so the goal of our project was to say ‘here are the best targets for observation’,” said Gillis Lowry, now a graduate student at San Francisco State University.

Fellow researcher Lucas Lawrence, now a graduate student at the University of Padua in Italy, said: “We wanted to create something that will enable other scientists to search effectively and we kept discovering new things about these worlds we wanted to investigate further.”

Using Telescopes to Search for Alien Atmospheres

Co-author Abigail Bohl, of Cornell University, emphasized that Earth, Venus, and Mars provide useful benchmarks for understanding habitability.

“We know Earth is habitable, while Venus and Mars are not. We can use our Solar System as a reference to search for exoplanets that receive stellar energy between what Venus and Mars get.

“Observing these planets can help us understand when habitability is lost, how much energy is too much, and which planets remain habitable — or maybe never were.

“The same idea applies to eccentric planets: how much orbital eccentricity can a planet have while still holding onto its surface water and habitable conditions?

“We identified planets at the inner and outer edges of the habitable zone, as well as those with the highest eccentricities, to test our understanding of what it takes for a planet to be and remain habitable. We also identified the targets that are most observable with the James Webb Space Telescope (JWST) and other telescopes.”

The team also matched different planets with observation methods to improve the chances of detecting signs of life.

Future Telescopes and the Search for Life

This curated list will guide astronomers using current and future observatories, including JWST, the Nancy Grace Roman Space Telescope (set to launch in 2027), the Extremely Large Telescope (set to see first light in 2029), the Habitable Worlds Observatory (expected to launch in the 2040s), and the proposed Large Interferometer For Exoplanets (LIFE) project.

According to Lowry, observing these small planets is essential to determine whether they have atmospheres and to refine models of habitability.

She noted that early analysis of the 10 planets receiving Earth-like radiation has already identified two strong candidates for near-term study: TRAPPIST-1 e and TOI-715 b.

The TRAPPIST-1 system is a major focus for JWST observations, led by Cornell astronomer Nikole Lewis. Both TRAPPIST-1 and TOI-715 b orbit small red stars, making it easier to detect and study their Earth-sized planets.

Full List of 45 Potentially Habitable Exoplanets Identified in the Paper

1. GJ 1002 b
2. GJ 1002 c
3. GJ 1061 c
4. GJ 1061 d
5. GJ 251 c
6. GJ 273 b
7. GJ 3323 b
8. GJ 667 C c
9. GJ 667 C e
10. GJ 667 C f
11. GJ 682 b
12. K2-239 d
13. K2-288 B b
14. K2-3 d
15. K2-72 e
16. Kepler-1229 b
17. Kepler-1410 b
18. Kepler-1544 b
19. Kepler-1606 b
20. Kepler-1649 c
21. Kepler-1652 b
22. Kepler-186 f
23. Kepler-296 e
24. Kepler-296 f
25. Kepler-441 b
26. Kepler-442 b
27. Kepler-452 b
28. Kepler-62 e
29. Kepler-62 f
30. L 98-59 f
31. LHS 1140 b
32. LP 890-9 c
33. Proxima Centauri b
34. Ross 508 b
35. TOI-1266 d
36. TOI-700 d
37. TOI-700 e
38. TOI-715 b
39. TRAPPIST-1 d
40. TRAPPIST-1 e
41. TRAPPIST-1 f
42. TRAPPIST-1 g
43. Teegarden’s Star c
44. Wolf 1061 c
45. Wolf 1069 b

“The transition to fatherhood often involves both positive experiences and a range of new stresses,” says Jing Zhou, PhD student at the Institute of Environmental Medicine, Karolinska Institutet, and co-first author of the paper. “Many cherish the intimate moments with their child, whilst at the same time the relationship with their partner may be affected and sleep quality may deteriorate, which can contribute to an increased risk of mental ill-health.”

Study Tracks Over 1 Million Fathers Across Sweden

The researchers analyzed data from more than one million fathers whose children were born in Sweden between 2003 and 2021. Using linked national registers, they followed when men received new psychiatric diagnoses, beginning one year before pregnancy and continuing until the child reached one year of age.

Depression and Stress Diagnoses Increase After One Year

The findings show that psychiatric diagnoses became less common during pregnancy and in the early months after birth compared with the year before pregnancy. By one year after birth, diagnoses related to anxiety and substance use had returned to levels seen before pregnancy. In contrast, depression and stress-related disorders showed a clear increase. These diagnoses rose by more than 30 percent compared with rates before pregnancy.

“The delayed increase in depression was unexpected and underscores the need to pay attention to warning signs of mental ill-health in fathers long after the birth of their child,” says Donghao Lu, senior lecturer and associate professor at the Institute of Environmental Medicine, Karolinska Institutet, and the paper’s corresponding author.

Timing Support for Fathers’ Mental Health

The researchers note that their results are based on clinical diagnoses, meaning men who did not seek care may not be included. Even so, the study highlights when fathers may be most vulnerable during early parenthood.

“By identifying periods of increased vulnerability, healthcare providers and other stakeholders can more easily offer support,” says Jing Zhou. “Postnatal depression is often discussed for new mothers, but fathers’ well-being is also important, both for themselves and for the whole family.”

The study was conducted in collaboration with Sichuan University in China and Uppsala University in Sweden. It was funded by Karolinska Institutet’s strategic research area in epidemiology and biostatistics, the Swedish Research Council and the European Research Council. The researchers report no conflicts of interest.