D-allulose more durably reduces body weight than oral semaglutide, while both equally increase grip strength in diet-induced obese mice

Source: National Library of Medicine February 23, 2026.

Authors: Yermek Rakhat, Sejya Banno, Dauren Zhantleu, Shin Tsunekawa, Daisuke Yabe, Yutaka Seino, Yusaku Iwasaki, Toshihiko Yada.

(Excerpt)

Abstract

Background

The rare sugar D-allulose, a zero-calorie sweetener, substantially ameliorates obesity.

It is reported to stimulate endogenous glucagon-like peptide 1 (GLP-1) release, which activates vagal afferents and directly affects neurons in the hypothalamic arcuate nucleus (ARH), thereby eliciting vagal and central nervous system (CNS) pathways.

D-allulose can now be produced on a large scale, which is expected to enable its use in dietary therapy.

The oral GLP-1 receptor agonist (GLP-1RA), *Oral Semaglutide (O-Sema), without injection, substantially ameliorates obesity.

It only activates CNS pathways. Thus, these GLP-1-based materials use common/distinct pathways, suggesting their common/distinct effects on obesity and related disorders, including sarcopenia.

(refers to the age-related reduction in muscle mass and strength, primarily in older age)

To investigate this, this study precisely compared their effects.

Methods

O-Sema and D-allulose were administered under identical conditions, at equivalent doses, via oral gavage and with food/water deprivation, to diet-induced obese mice.

Acute and subchronic effects on food intake, body weight, and grip strength were measured.

Results

D-allulose acutely reduced food intake rapidly, and O-Sema reduced it slowly.

Subchronically, D-allulose and O-Sema significantly reduced food intake and body weight during the early treatment phase (Days 0–3).

Weight loss was reduced with O-Sema, but with D-allulose, it persisted in the later period (Days 4–10) and even after treatment completion.

D-Allulose and O-Sema increased muscle strength

Mechanistically, D-allulose and semaglutide similarly activated anorexigenic leptin-responsive neurons, while only D-allulose significantly suppressed orexigenic ghrelin-responsive neurons in ARH.

Conclusions

D-allulose and O-Sema both cause weight loss, likely via the CNS pathway, including the activation of anorexigenic neurons in the ARH.

Weight loss is restored with O-Sema, while it can be maintained with D-allulose, likely through a combination of vagal afferent and CNS pathways, including the inhibition of orexigenic neurons in the ARH.

Their optimal use could potentially provide precise control over obesity and related disorders.

Read more..

This figure illustrates the mechanisms of action for weight loss and appetite regulation of Semaglutide (a GLP-1 receptor agonist) and Allulose via the gut-brain axis.

The essence of the process is that these substances send "satiety" signals to the brain through different pathways, which ultimately leads to a reduction in food intake and body weight.

Effect of Semaglutide

Semaglutide (O-Sema), marked in green, primarily acts directly:

• It crosses the blood-brain barrier.

• It directly stimulates leptin-sensitive neurons in the hypothalamus (Leptin-sens. Neuron) in the arcuate nucleus (ARH).

• This process is mainly responsible for the induction (initial) phase of weight loss.

Effect of Allulose

Allulose, marked in red, acts in a more complex way through two main pathways:

1. Direct brain effect

Similar to Semaglutide, it enters the hypothalamus, where it inhibits ghrelin-sensitive neurons responsible for hunger and stimulates leptin-sensitive neurons responsible for satiety.

2. Indirect intestinal effect

In the gut, it stimulates the release of GLP-1.

This hormone sends a signal via the vagal afferents to the NTS (Nucleus Tractus Solitarius) center in the medulla oblongata.

Induction and Maintenance

The figure distinguishes between two phases of weight loss:

• Induction

Occurs primarily through the activation of hypothalamic (ARH) neurons.

• Maintenance

In this phase, signals arriving at the NTS (via the vagus nerve) and the hypothalamus together ensure long-term weight loss.

Daily food intake, body weight and weight gain chart

Based on the data presented in these graphs, the study compares the effects of once-daily oral administration of D-allulose and oral semaglutide (O-Sema) on diet-induced obese (DIO) mice.

*What is a "DIO mouse"?

DIO = Diet-Induced Obesity

• A DIO mouse is a mouse model fed a very high-fat diet (usually around 60% of the diet's energy from fat), leading to significant weight gain and obesity over several months.
• In such a model, body weight can increase by more than 100%, and research is conducted to study insulin resistance, diabetes, fatty liver, and other obesity-related diseases.

The graphs show that both treatments significantly reduce food intake and body weight compared to the control group (DW), but D-allulose provides a more sustained weight loss effect during the 16-day treatment and post-treatment period.

Main observations from the graphs

Daily food intake (Graph A)

Both D-allulose and O-Sema cause a sharp, significant reduction in food intake in the early treatment phase (Days 0–3).

By the end of the treatment period (around Day 10), food intake in both groups begins to return to control levels.

Body weight (Graph B) and weight gain (Graph C)

• Initial phase (Days 0–3)

Both O-Sema and D-allulose cause similar, steep body weight loss.

• Late phase (Days 4–10)

In the D-allulose group, weight loss continues, while the O-Sema group shows a plateau or a slight "rebound" effect, where weight loss is less pronounced compared to the initial drop.

• Post-treatment phase (Days 11–16)

After treatment cessation, the D-allulose group maintains significantly lower body weight and less weight gain compared to the control group.

In contrast, the O-Sema group shows a quicker return to control weight.

Scientific context

Research indicates that while both substances activate anorexigenic (appetite-reducing) neurons in the brain, D-allulose may have a more sustained effect as it also inhibits orexigenic (appetite-stimulating) neurons and utilizes additional pathways, such as vagal afferent signaling.

The effect of O-Sema on body weight in this specific mouse model appears to be more transient after the initial treatment phase is complete.

* Oral Semaglutide

Semaglutide is an active ingredient primarily used to treat type 2 diabetes and promote weight loss, but its research and clinical applications are also expanding in the areas of metabolic organs (liver) and the cardiovascular system.

What is Semaglutide?

Semaglutide is a GLP-1 receptor agonist peptide, meaning it mimics the action of naturally occurring glucagon-like peptide-1 (GLP-1) in the body.

Forms of administration

Once-weekly subcutaneous injection in the arm or abdomen (e.g., Ozempic, Wegovy), or oral tablet (e.g., Rybelsus).

What is it used for?

It has two main indications:

• Type 2 diabetes: Along with diet and exercise, it improves blood sugar control, aids insulin secretion, and inhibits glucagon secretion.
• Obesity/overweight management: For adults with BMI ≥ 30, or ≥ 27 in the normal upper category with weight-related comorbidities (e.g., diabetes, hypertension, dyslipidemia).

Newer studies show it is also effective in treating metabolic dysfunction-associated steatotic hepatitis (MASH), with a response rate of almost two-thirds in patients.

How does it affect the body?

Semaglutide reduces body weight and blood sugar through multiple mechanisms:

• Increases insulin secretion, decreases glucagon secretion,
• Slows gastric emptying,
• Reduces appetite through a central nervous system effect.

It also favorably modifies the lipid profile and cardiovascular risk profiles, thus reducing the risk of cardiovascular events in an appropriate population.

Side effects and safety

The most commonly reported side effects are gastrointestinal:

• Nausea, vomiting,
• Abdominal pain, diarrhea,
• Constipation.

Newer data suggest that a relatively low percentage of patients treated with semaglutide end up in the emergency department due to these effects, and in most cases, these are gastrointestinal symptoms, less frequently hypoglycemia or allergic reactions.

Important medical considerations

Semaglutide is a strictly prescription-only medication and, according to professional guidelines, is a diabetes drug, not a "weight-loss bonus drug" (although its weight-reducing effect is strong).