A New Discovery May Help Break the Weight Loss Plateau
Anyone who’s tried to lose weight by cutting calories knows how frustrating it can be when progress suddenly stalls. At first, the pounds come off easily, but then your body seems to hit the brakes. This happens because the body senses a drop in calorie intake and responds by slowing down metabolism, burning fewer calories to conserve energy.
It’s an ancient survival mechanism: the body perceives a potential starvation threat and adapts by holding on to calories, even when the goal is intentional weight loss. Unfortunately, this means that despite your best efforts, your body may work against you.
Now, researchers at the University of Southern Denmark have identified a potential way to keep metabolism high even when calorie intake is reduced, a breakthrough that could help people push past weight loss plateaus.
A Potential Boost for Weight-Loss and Diabetes Treatments
This discovery could be especially meaningful for those using weight-loss or diabetes medications like Wegovy and Ozempic. Many people on these medications lose about 20–25% of their body weight before hitting a plateau, where further weight loss becomes difficult.
It may go well at first, but as people lose some of the weight they aim to shed, their progress stalls because the body's metabolism adapts. Not to mention a reduction is muscle mass resulting in a reduced metabolic rate.
A Surprising Gene Discovery
A new study, published in *Cell Metabolism*, focuses on a gene called PLVAP (plasmalemma vesicle-associated protein).
Humans born without the PLVAP gene often have issues with lipid metabolism, a connection the researchers aimed to explore further. What they found was that the PLVAP gene helps the liver switch from burning sugar to burning fat during fasting.
When the researchers turned off the PLVAP gene in mice, the liver stopped recognizing the fasting state and continued burning sugar instead of fat. This created a shift in how energy was processed in the body, with surprising benefits.
How It Works
Without the PLVAP gene, the liver didn’t absorb fat as expected during fasting. Instead, the fat was redirected to the skeletal muscles, where it was efficiently used for energy. The mice showed improved insulin sensitivity and lower blood sugar levels, without any negative side effects.
This discovery suggests that manipulating the PLVAP gene (or finding a way to mimic its effect) could help people continue burning fat even after initial weight loss.
While direct modulation of the PLVAP gene through lifestyle interventions like exercise has not been established, certain signaling pathways known to regulate PLVAP expression may be influenced by physiological factors. Research indicates that PLVAP expression can be indirectly modulated by various compounds and signaling molecules.
To indirectly influence the signaling pathways known to regulate PLVAP expression, you can target the following key regulators through specific lifestyle strategies, including diet, exercise, and stress management:
1. Vascular Endothelial Growth Factor (VEGF) Pathway
VEGF is crucial for angiogenesis (the formation of new blood vessels) and is known to upregulate PLVAP expression. You can naturally boost VEGF levels through:
✅ Exercise (especially HIIT and endurance training)
Intense aerobic and resistance exercise stimulates VEGF production by increasing hypoxia-inducible factor 1-alpha (HIF-1α), which drives VEGF expression.
Try combining HIIT (short bursts of high-intensity effort) with moderate-intensity steady-state cardio.
✅ Dietary Strategies
Nitric oxide (NO) production supports VEGF activity. You can increase NO levels by consuming:
Leafy greens (spinach, arugula, kale)
Beets and beetroot juice
Pomegranate
Citrulline-rich foods (watermelon)
Polyphenols from berries, dark chocolate, and green tea also enhance VEGF expression.
✅ Hypoxic training
Training in low-oxygen environments (like altitude training or mask-based hypoxic training) can stimulate VEGF by triggering HIF-1α activation.
2. Angiotensin II Pathway
Angiotensin II is involved in regulating blood pressure and vascular tone, and it can influence PLVAP expression.
✅ Exercise
High-intensity exercise increases angiotensin II production, but chronic elevation can be harmful. Maintaining balance is key.
Moderate resistance and aerobic exercise are ideal for optimizing angiotensin II signaling without overloading the system.
✅ Potassium-Rich Diet
Potassium helps regulate the renin-angiotensin-aldosterone system (RAAS), which influences angiotensin II production. Include:
Bananas
Sweet potatoes
Avocados
Spinach
✅ Reduce Sodium Intake
Excess sodium increases angiotensin II levels, so keep sodium intake moderate (~2,300 mg/day).
3. Inflammatory Mediators (TNF-α, IL-6)
Chronic inflammation can upregulate or dysregulate PLVAP expression. Modulating inflammation through diet, exercise, and lifestyle choices can help:
✅ Anti-Inflammatory Diet
Omega-3 fatty acids (found in flaxseeds, chia seeds, walnuts, and algae oil) reduce TNF-α and IL-6.
Curcumin (from turmeric) and ginger have anti-inflammatory effects.
Antioxidant-rich foods (like berries, dark leafy greens, and dark chocolate) help neutralize inflammation.
✅ Strength Training and Moderate Cardio
Regular exercise reduces baseline TNF-α and IL-6 levels.
High levels of cortisol (from overtraining) can increase inflammation, so balance intense sessions with recovery.
4. Gsα/cAMP/CREB Signaling Pathway
The cAMP/CREB pathway is involved in cellular energy balance and metabolic regulation.
✅ Exercise
Exercise (especially HIIT and strength training) boosts cAMP levels by activating β-adrenergic receptors.
Cold exposure (e.g., cold showers or ice baths) also stimulates cAMP production.
✅ Dietary Boosters
Caffeine increases cAMP by inhibiting phosphodiesterase (PDE), which breaks down cAMP.
Green tea (EGCG) enhances cAMP signaling.
Forskolin (from Coleus forskohlii) is a natural cAMP booster — available as a supplement.
5. Stress and Sleep Management
Chronic stress and poor sleep can disrupt most of these pathways.
✅ Stress Reduction
Mindfulness, meditation, and deep breathing reduce cortisol and inflammatory cytokines.
Lowering cortisol helps maintain proper metabolic and vascular signaling.
✅ Sleep Optimization
Aim for 7–9 hours of quality sleep to regulate inflammatory markers and metabolic health.
Proper sleep enhances VEGF and cAMP activity.
✅ Summary of Practical Actions
Pathway | How to Enhance It |
VEGF | HIIT, beets, leafy greens, polyphenols, hypoxic training |
Angiotensin II | Moderate exercise, potassium-rich foods, reduce sodium |
Inflammation | Omega-3s, curcumin, strength training, antioxidants |
cAMP/CREB | HIIT, caffeine, forskolin, cold exposure |
Stress Response | Meditation, quality sleep, deep breathing |
New Insights into Liver Metabolism
It is well known that elevated blood sugar may lead to chronic complications for people with type 2 diabetes. Understanding PLVAP could help diabetics better regulate their blood sugar in the future.
If future studies confirm similar effects in humans, this research could revolutionize weight-loss treatments, helping people sustain fat burning and break through the frustrating plateau that so often derails progress.
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