One approach that has drawn growing interest is intermittent energy restriction (IER), a form of dieting in which periods of reduced calorie intake are followed by periods of more typical eating. Research published in 2023 suggests that this strategy may do more than reduce body weight. It may also shift the relationship between gut bacteria and brain activity in ways that are closely tied to appetite and food behavior.

“Here we show that an IER diet changes the human brain-gut-microbiome axis. The observed changes in the gut microbiome and in the activity in addition-related brain regions during and after weight loss are highly dynamic and coupled over time,” said last author Dr. Qiang Zeng, a researcher at the Health Management Institute of the PLA General Hospital in Beijing.

Intermittent fasting and the brain

To explore what happens inside the body during weight loss, the researchers studied 25 adults with obesity in China. The volunteers, who were about 27 years old on average, had a BMI between 28 and 45.

The team used several tools to track changes over time. Stool samples were analyzed with metagenomics to measure the composition of the gut microbiome. Blood tests were used to monitor metabolic and physiological changes. The researchers also used functional magnetic resonance imaging (fMRI) to examine activity in brain regions involved in appetite, emotion, attention, learning, inhibition, and reward.

“A healthy, balanced gut microbiome is critical for energy homeostasis and maintaining normal weight. In contrast, an abnormal gut microbiome can change our eating behavior by affecting certain brain area involved in addiction,” explained coauthor Dr. Yongli Li from the Department of Health Management of Henan Provincial People’s Hospital in Henan, China.

A carefully controlled weight loss program

The study began with a 32 day high controlled fasting phase. During this period, participants received meals designed by a dietitian. Their calorie intake was gradually reduced in steps until it reached about one quarter of their basic energy needs.

This was followed by a 30 day low controlled fasting phase. During this stage, participants were given a list of recommended foods rather than fully prepared meals. Those who followed the plan exactly would consume 500 calories per day for women and 600 calories per day for men.

By the end of the intervention, participants had lost an average of 7.6 kilograms, equal to about 7.8% of their starting body weight. They also had reductions in body fat and waist circumference.

The metabolic improvements extended beyond weight. Blood pressure fell, as did fasting plasma glucose, total cholesterol, HDL, LDL, and the activity of key liver enzymes. According to the researchers, these changes suggest that intermittent energy restriction may help reduce obesity related problems such as hypertension, hyperlipidemia, and liver dysfunction.

Brain and gut changes moved together

The researchers found that the weight loss program was linked to lower activity in several brain regions involved in appetite and addiction related behavior. These changes may help explain why dieting affects not only body size, but also food cravings, self control, and the drive to eat.

At the same time, the gut microbiome shifted. The abundance of Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis rose sharply. Escherichia coli decreased.

Further analysis suggested that certain microbes were connected with activity in specific brain areas. The abundance of E. coli, Coprococcus comes, and Eubacterium hallii was negatively associated with activity in the brain’s left orbital inferior frontal gyrus, a region involved in executive function and willpower during weight loss.

Other bacteria showed the opposite pattern. P. distasonis and Flavonifractor plautii were positively linked with brain regions involved in attention, motor inhibition, emotion, and learning.

These findings point to a striking possibility: as people lose weight, the gut microbiome and the brain may change together. The study cannot prove whether gut bacteria drive the brain changes, whether the brain drives microbial changes, or whether another factor influences both. Still, the results add to evidence that weight control is not just a matter of willpower or calories. It may involve a changing biological conversation between the gut and the brain.

A two way conversation inside the body

“The gut microbiome is thought to communicate with the brain in a complex, two-directional way. The microbiome produces neurotransmitters and neurotoxins which access the brain through nerves and the blood circulation. In return the brain controls eating behavior, while nutrients from our diet change the composition of the gut microbiome,” said coauthor Dr. Xiaoning Wang from the Institute of Geriatrics of the PLA General Hospital.

This two way communication may help explain why obesity is so difficult to treat. Hunger, cravings, mood, reward, and metabolism are all shaped by biological signals. The gut microbiome can produce compounds that influence inflammation, metabolism, and nervous system activity. The brain, in turn, helps regulate food choices and eating behavior.

The 2023 findings suggest that successful weight loss may involve changes across this entire system rather than in one isolated organ.

What later research adds

Research published after the 2023 study has continued to support the idea that fasting can influence the gut microbiome, although the evidence remains complex. A 2024 systematic review of human studies found that intermittent fasting appears to affect gut microbial richness, diversity, and composition. However, the authors also noted that results varied widely between studies, and more research is needed to determine which changes are truly beneficial for health.

Another 2024 clinical study compared intermittent fasting combined with protein pacing to continuous calorie restriction in adults with overweight or obesity. Both diets reduced calorie intake, but the fasting and protein pacing group showed greater weight loss and more pronounced shifts in the gut microbiome. The researchers reported increases in microbes and metabolic signals associated with improved body composition and fat loss.

Together, these later findings strengthen the broader picture: fasting based interventions may reshape the gut microbiome in meaningful ways. However, they also show that the details matter. The type of fasting, calorie intake, protein intake, fiber intake, meal timing, and individual biology may all influence the outcome.

The next question for weight loss research

The original 2023 study was small and correlational, so it cannot show cause and effect. It also focused on a specific group of participants and a short term intervention. Larger and longer studies will be needed to determine whether certain microbes or brain regions can reliably predict who will lose weight, who will keep it off, and which diets work best for different people.

Coauthor Dr. Liming Wang, likewise from the Health Management Institute in Beijing, said: “The next question to be answered is the precise mechanism by which the gut microbiome and the brain communicate in obese people, including during weight loss. What specific gut microbiome and brain regions are critical for successful weight loss and maintaining a healthy weight?”

For now, the research offers a more detailed view of what may happen during intermittent fasting. Weight loss may not be limited to shrinking fat stores. It may also involve a synchronized shift in gut bacteria, metabolism, and brain activity that changes how the body responds to food.

The work was funded by FAPESP and focused on Goto-Kakizaki rats, a well established animal model used to study non-obese type 2 diabetes. Type 2 diabetes is marked by high blood sugar that occurs when insulin, the hormone that helps move glucose from the blood into cells, does not work effectively.

Fish Oil and Insulin Resistance

Omega-3 supplements, including fish oil, are often used by people with cardiovascular disease and type 2 diabetes. However, scientists still know much less about how these fatty acids affect insulin resistance when obesity is not involved.

That question matters because obesity is one of the strongest risk factors for type 2 diabetes, but it is not the whole story. An estimated 10% to 20% of people with type 2 diabetes worldwide are not obese. For these patients, the biological roots of insulin resistance may differ from the better known obesity-linked pathways.

In the study, researchers gave the rats fish oil at a dose of 2 grams per kilogram of body weight (equivalent to 540 mg/g of eicosapentaenoic acid, or EPA, and 100 mg/g of docosahexaenoic acid, or DHA) three times weekly for eight weeks. By the end of the experiment, the treated animals showed lower insulin resistance, better blood sugar control, reduced inflammatory markers, and improvements in several lipid measures, including total cholesterol, LDL (“bad cholesterol”) and triglycerides.

The results came from preclinical experiments, so they do not prove that fish oil will have the same effects in people. Still, the findings point to inflammation as a powerful target in non-obese diabetes and suggest that omega-3 fatty acids deserve closer study in this group.

A Shift in Immune Cells

“Our experiments involved Goto-Kakizaki [GK] rats, an animal model for non-obese type 2 diabetes. We found that insulin resistance can be reduced in these animals by modulating the inflammatory response so as to change the profile of defense cells [lymphocytes] from a pro-inflammatory state to an anti-inflammatory state. This process parallels the response of obese individuals with insulin resistance to omega-3 fatty acid supplementation,” said Rui Curi, Director of Butantan Institute’s Education Center, Professor of Interdisciplinary Graduate Studies in Health Sciences at Cruzeiro do Sul University (UNICSUL), and coordinator of the study.

Lymphocytes are white blood cells that help direct the adaptive immune response. When their behavior changes, the effects can spread through the immune system and influence other cells involved in inflammation.

“In previous studies, we observed alterations in both lymphocytes and macrophages [large white blood cells that often reside in adipose tissue and are part of the innate immune system, engulfing and destroying pathogens] in non-obese rats with insulin resistance. In such cases, these cells produce more pro-inflammatory cytokines, as is central in obese people with diabetes,” Curi explained.

“The main aim of the study, therefore, was to find out whether supplementation with fish oil [rich in omega-3] could reverse specific alterations in lymphocytes that had been observed in previous research. Our findings increased our knowledge of the link between inflammation and insulin resistance in non-obese animals, confirming that this is a key factor in diabetes even in the absence of obesity,” said Renata Gorjão, last author of the article, and Co-Director of UNICSUL’s Program of Graduate Studies in Health Sciences.

Inflammation Without Obesity

The Nutrients study, conducted during the PhD candidacy of Tiago Bertola Lobato, was part of a broader FAPESP-supported project exploring how insulin resistance develops in non-obese animals.

Curi noted that obesity is a major diabetes risk factor, but not the only one. In people who develop diabetes without obesity, one leading hypothesis is that genetic factors may play an important role. In another study published in Cells, Curi, Gorjão, and colleagues investigated whether delayed intestinal transit might also contribute to insulin resistance in non-obese individuals.

“Most obese people have chronic low-level inflammation, which is known to affect the insulin signaling pathways. Adipose tissue, which is augmented in obesity, releases pro-inflammatory cytokines that affect the insulin signaling pathways, promoting insulin resistance. In the non-obese model, this impactful characteristic of adipose tissue is absent, but systemic inflammation is present,” Curi said.

The group had previously shown systemic inflammation in non-obese GK rats with insulin resistance in a study published in the International Journal of Molecular Sciences.

Another paper from the same project reported that anti-inflammatory defenses appear to break down early in non-obese GK rats with insulin resistance. Lymph nodes (part of the immune system) from newly weaned 21-day-old GK pups already showed reduced markers of regulatory T-cells (Tregs, cells with anti-inflammatory characteristics). The researchers also detected other early inflammatory changes. That work was published in FEBS Letters, a journal of the Federation of European Biochemical Societies.

How Omega-3s May Help

The Nutrients study suggests that fish oil may work by moving immune activity away from a damaging inflammatory pattern and toward a more protective one.

“Fish oil supplementation reversed this pro-inflammatory profile, displaying a significant anti-inflammatory effect and reducing polarization of Th1 and Th17 cells [lymphocyte subtypes that perform crucial functions in inflammation], followed by a rise in the percentage of Tregs, which can inhibit the activation of pro-inflammatory lymphocytes. Thus the action of omega-3 fatty acids on lymphocytes, modulating them from a pro-inflammatory state to an anti-inflammatory state, may have triggered the reduction in insulin resistance in these animals,” Lobato said.

That immune shift is important because insulin resistance is not only a problem of sugar metabolism. It is also deeply connected to inflammation. When inflammatory signals remain elevated, they can interfere with insulin signaling and make it harder for cells to respond to the hormone.

The study adds to a growing view of type 2 diabetes as a disease shaped by both metabolism and the immune system. In this case, fish oil appeared to improve blood sugar regulation not simply by changing fat levels, but by changing the inflammatory environment that helps drive insulin resistance.

What Later Studies Add

Since the Nutrients paper was published, related human research has continued to examine how omega-3 fatty acids may influence early diabetes risk and metabolic health.

A 2025 double blind randomized controlled trial in Food and Function tested fish oil supplementation in healthy middle aged and older adults. Over 12 weeks, the fish oil groups had dose related increases in serum EPA and DHA. The researchers also reported decreases in fasting insulin and the HOMA-IR index, a common marker of insulin resistance. Fasting blood glucose trended downward across groups, and several lipid related measures also improved.

Another 2024 analysis in Nutrition and Diabetes used modeling data from 161 patients with type 2 diabetes to explore the relationship between omega-3 levels and HbA1c, a longer term marker of blood sugar control. The authors reported a dose related association and proposed that omega-3 intake could be studied in a more individualized way, while also noting that the role of omega-3s in type 2 diabetes remains debated.

Together, these studies do not settle the question of whether fish oil should be used to manage diabetes. Human evidence remains mixed, and the Brazilian study was conducted in animals, not people. However, the newer findings are consistent with the idea that omega-3 fatty acids may affect insulin resistance and inflammation in ways worth testing more carefully.

More Research Still Needed

Despite the promising findings, the researchers stressed that the results should be interpreted cautiously. Animal studies are useful for uncovering biological mechanisms, but clinical trials are needed before scientists can know whether the same strategy works in people with non-obese type 2 diabetes.

“These studies involved well-established experimental models that mimic insulin resistance in non-obese individuals. Trials in humans are needed to estimate the ideal dose and the most indicated type of omega-3 fatty acid,” Curi said.

For now, the study offers a compelling clue: in diabetes, body weight may not be the only driver of insulin resistance. Inflammation can play a central role even without obesity, and fish oil may help reveal how that hidden process can be changed.

Many researchers believe the next major advance will come not from shrinking devices further, but from building upward.

A team led by University of Illinois Grainger College of Engineering materials science and engineering professor Qing Cao has demonstrated a new method for stacking multiple layers of silicon electronics directly on top of one another. The approach could dramatically increase computing density, improve performance, and reduce energy consumption while extending the progress that has driven the semiconductor industry for more than half a century.

“Take something as simple as static random-access memory, which is universal in CPUs and GPUs. Today it takes six microelectronic devices called transistors on a single plane to store one bit of information. With vertical integration, you can distribute them across multiple layers. It’s like replacing a sprawling suburb with high-rises: you get the same functionality, but the spatial footprint is reduced while making communication between layers faster and more efficient,” Cao explained.

The researchers report that their process achieves device yields of 98‒100% while using standard single-crystalline silicon, the semiconductor material that underpins modern electronics. The results suggest the technique could eventually be adopted by commercial chip manufacturers.

“Vertical integration is already starting to make its way into commercial devices, particularly in specialized AI hardware, but monolithic integration is what unlocks the full promise of 3D chips,” Cao said. “For the first time, we have met the thermal budget of monolithic 3D integration using standard single-crystalline silicon and delivered unprecedented performance.”

The findings were published in Nature, a journal that rarely features silicon microelectronics research articles.

Why the Semiconductor Industry Is Looking Upward

For roughly 60 years, Moore’s law has guided chip development. The principle predicts that transistor density on integrated circuits will double about every two years, leading to faster and more efficient processors.

That trend has held remarkably well, but it is becoming increasingly difficult to sustain.

“In a sense, we’re hitting a limit imposed by physics,” Cao said. “If you look at the actual size of transistors, they’re not getting smaller, especially in terms of their contacted gate pitch. This is because we’re becoming limited by the intrinsic material properties of silicon and the fundamental rules of quantum mechanics. If we’re going to keep up the trend of increasing processing power of our microprocessors, we have to start thinking beyond just squeezing more devices on a single surface.”

Stacking devices vertically offers an attractive alternative. Instead of continuing to shrink individual transistors, engineers can place multiple layers of circuits on top of one another. This not only creates more room for components but also shortens wiring distances, reducing parasitic capacitance and significantly increasing communication bandwidth between different parts of a chip.

Those advantages are particularly important for artificial intelligence and other data-intensive computing applications.

The Promise of Monolithic 3D Chips

Current commercial 3D chip technologies already use stacking, but they typically involve manufacturing semiconductor devices on separate wafers before bonding them together. Examples include high-bandwidth memory and AMD’s 3D V-Cache technology.

While successful, these methods have limitations. Alignment between layers is relatively coarse, and the vertical connections known as through-silicon vias (TSVs) are comparatively large and sparse.

Monolithic three-dimensional integration takes a different approach. Rather than joining completed wafers, each new device layer is fabricated directly on top of the previous one. This allows much denser vertical connections, smaller distances between layers, and alignment accuracy measured in nanometers.

Researchers have pursued this concept for years because it could increase interlayer connectivity by a factor of 10 to 100 compared with conventional stacking methods.

Solving the Heat Problem

The biggest obstacle to monolithic integration has been temperature.

Producing high-quality crystalline silicon and fabricating high-performance semiconductor devices typically requires temperatures approaching 1,000 degrees Celsius. However, once metal interconnects are already present in a completed circuit layer, such temperatures would destroy them.

“Generally, the industry accepts that once the first layer of circuits is complete, the thermal budget limit for any additional layers is 400 degrees Celsius,” Cao said. “Researchers in both academia and industry have tried to get around this by working with semiconductor materials other than single-crystalline silicon for the upper layers. But the resulting devices all inevitably suffer from issues with performance and reliability.”

Previous efforts have explored alternatives including polycrystalline silicon, amorphous and nanocrystalline metal oxides, carbon nanotubes, and two-dimensional semiconductors. However, those materials often introduce performance limitations or defects that create a mismatch with the silicon transistors in the bottom layer.

Ultrathin Silicon Nanomembranes Enable Low Temperature Manufacturing

The Illinois team developed a process that preserves the advantages of single-crystal silicon while staying well below the thermal limit.

The method begins by creating ultrathin freestanding silicon nanomembranes from a donor wafer. These membranes are then transferred onto a receiving substrate that already contains completed circuitry using a roll laminator. The bonding process requires temperatures of no more than 200 degrees Celsius.

Because the silicon layers retain their crystalline quality, the resulting devices maintain strong performance and reliability while remaining safely within the thermal budget required for monolithic integration.

“Our method is not only easier to implement with lower cost, but it has several advantages over previous approaches to stack silicon wafers,” Cao said. “The membranes we transferred are only 10 nanometers thick or less, compared to the 500 to 700 micrometers thickness of a typical wafer. Because they are thin, these membranes are mechanically flexible to conform to the underlying surface. This conformality helps avoid interfacial defects like voids, which are common when trying to force two rigid wafers together via wafer bonding.”

High Performance With Three Stacked Layers

The researchers also redesigned the transistor architecture.

Traditional transistor manufacturing relies on a process called doping, which introduces impurities into silicon to control electrical behavior. That process usually requires temperatures above 600 degrees Celsius.

To avoid those temperatures, the team used junctionless transistors. In these devices, the silicon is uniformly and heavily doped before the stacking process begins. The extremely thin silicon films still allow effective control by the transistor gate, while the high doping levels help reduce parasitic contact resistance.

Using this strategy, the researchers fabricated three stacked layers containing 625 transistors each. The devices showed strong uniformity and high manufacturing yield.

Their output current densities matched those of conventional silicon transistors fabricated on bulk wafers at much higher temperatures. They also outperformed monolithic devices made from alternative materials by at least a factor of three to four.

The team connected the layers using vertical metal interconnects and successfully demonstrated three-dimensional logic circuits as well as static random-access memory cells.

Toward Commercial Semiconductor Manufacturing

According to Cao, the most significant result may be the scalability of the process.

“But most importantly, we’ve shown that this process is scalable,” Cao said. “You can keep stacking layers beyond the three we demonstrated. And the process will yield high-performing transistors with high yield and low variability. We now have a strong foundation for transferring this technology and demonstrating its immediate promise in an industrial semiconductor foundry.”

The work was carried out through Illinois Grainger Engineering’s Center for Advanced Semiconductor Chips with Accelerated Performance, whose industry partners include IBM, Intel, and the Taiwan Semiconductor Manufacturing Company.

The researchers are now preparing to transfer the technology to an industrial semiconductor foundry, an important step toward bringing true monolithic 3D silicon chips into commercial production.

Additional contributors to the study included Bao Lam, Yung Man Yu, Hyunjun Nam, Hsu-Chih Ni, Shomik Chatterjee, Shaloo Rakheja, and Jian-Min Zhuo.

Funding was provided by the National Science Foundation, industry partners of Illinois Grainger Engineering’s Center for Advanced Semiconductor Chips with Accelerated Performance, and the Silicon Crossroads Microelectronics Commons Hub.

The findings point to a possible way to counter one of the hidden biological effects of working through the night. However, the researchers stress that larger studies are needed before melatonin can be recommended as a long-term strategy for reducing cancer risk in night shift workers.

How Night Shifts Disrupt the Body

Melatonin is best known as the hormone that helps regulate sleep. It rises in darkness and signals to the body that it is time to rest. For people who work overnight, that natural rhythm can be disrupted.

Normal night-time melatonin production is often suppressed in night shift workers. According to the researchers, this may weaken the body’s ability to repair oxidative DNA damage, a type of cellular wear and tear that occurs as part of normal metabolism.

That matters because reduced DNA repair may be one pathway linking long-term night shift work with higher risk for certain cancers. Night shift work has also drawn attention from major health agencies because of its effects on the body’s internal clock, sleep patterns, light exposure, and hormone signaling.

Testing Melatonin in Night Shift Workers

To explore whether melatonin could improve DNA repair, researchers conducted a randomized placebo controlled trial involving 40 night shift workers.

Half of the participants took a 3 mg melatonin pill once daily for 4 weeks. They took the supplement with food about 1 hour before going to sleep during the day. The other half took a 3 mg placebo pill on the same schedule.

All participants had been working at least two consecutive night shifts each week for at least 6 months. Each shift lasted at least 7 hours. None of the participants had sleep disorders or long-term health conditions.

A Marker of DNA Repair Rose During Daytime Sleep

The researchers collected urine samples during two study periods. One sample period took place before the trial began, and the other occurred near the end of the 4 week intervention. Samples were collected during daytime sleep after night shift work and during the following night shift.

Participants also wore activity trackers so the researchers could measure how long they slept during the day.

The team measured urinary levels of 8-OHdG, a marker used to assess oxidative DNA damage repair capacity. Higher urinary levels during sleep were interpreted as a sign of greater repair activity.

Among workers who took melatonin, urinary 8-OHdG levels were 80% higher during daytime sleep compared with those who took the placebo. That suggests melatonin may have boosted DNA repair while participants were sleeping after night work.

However, the same effect was not seen during the subsequent night shift. During that period, urinary 8-OHdG levels did not differ significantly between the melatonin and placebo groups.

Why the Findings Matter

The study offers a possible explanation for how melatonin might help reduce some of the biological strain caused by working at night. The body normally uses sleep and circadian timing to coordinate repair processes. When people work overnight and sleep during daylight hours, that system may not function as well.

Melatonin may help restore part of that lost signal, at least during daytime sleep. Still, the study was small and short, and it did not measure cancer outcomes. It only measured a biomarker related to DNA repair.

Most participants also worked in healthcare, which means the results may not apply to all night shift workers. The researchers were also unable to account for natural light exposure, which can affect melatonin levels in the body.

Newer Context on Night Shift Work

Since the trial was published in 2025, broader research has continued to highlight the complex ways night shift work may affect health. Recent reviews have pointed to several possible mechanisms, including circadian disruption, altered hormone signaling, changes in immune function, metabolic disruption, and impaired DNA repair.

Major scientific assessments have also treated persistent night shift work and light at night as important public health concerns. The International Agency for Research on Cancer has classified night shift work as probably carcinogenic to humans, and the National Toxicology Program has reviewed evidence linking persistent night shift work and light at night with cancer risk.

These findings do not prove that melatonin supplements prevent cancer. Instead, they strengthen the rationale for studying whether restoring melatonin signaling could help reduce some of the biological effects of long-term night work.

Researchers Urge Caution

The researchers emphasize that their findings should be tested in larger studies involving different doses and longer follow up periods.

They write: “Increased oxidative DNA damage due to diminished DNA repair capacity is a compelling mechanism that may contribute to the carcinogenicity of night shift work. Our randomized placebo-controlled trial suggested melatonin supplementation may improve oxidative DNA damage repair capacity among night shift workers.”

And they conclude: “Our findings warrant future larger-scale studies that examine varying doses of melatonin supplements and longer-term impacts of melatonin use. Pending the outcome of such studies, melatonin supplementation may prove to be a viable intervention strategy to reduce the burden of cancer among night shift workers.”

They add: “Assessing long-term efficacy is critical since those who work night shifts for many years would need to consistently consume melatonin supplements over that time frame to maximize the potential cancer prevention benefits.”

For now, the results suggest that melatonin may do more than support sleep. It may also help night shift workers activate a key repair process while their bodies recover during the day. But whether that translates into meaningful long-term protection remains an open question.