Browse the evidence

Systemic inhibition of the chromatin modifier LSD1 using GSK-LSD1 or SP2509 reduces body weight, improves insulin sensitivity, and reverses nonalcoholic fatty liver disease (NAFLD) in obese mouse models, independent of reduced food intake.

Targeting the enzyme LSD1 appears to fix the underlying metabolic dysfunction in obesity, not just cause weight loss. It reduces fat tissue inflammation and stops fat from flooding the liver, improving insulin sensitivity directly. This suggests that future drugs targeting LSD1 could treat obesity and its complications like fatty liver and diabetes simultaneously, rather than just suppressing appetite.

Housing mice at thermoneutrality (30°C) rather than standard room temperature (22°C) does not improve the prediction of human drug efficacy for weight loss, as the direction and magnitude of drug effects vary by mechanism regardless of temperature.

This paper is a methodological critique for preclinical researchers, not a direct guide for human behavior. It suggests that while standard mouse housing (22°C) creates thermal stress, simply moving to thermoneutrality (30°C) does not solve the translatability problem for obesity drugs. Researchers should test drugs at both temperatures to understand mechanism-specific responses, as efficacy can flip depending on the thermal environment.

GLP-1 receptor agonists (like semaglutide) and hFGF21 analogs produce similar weight loss efficacy in mice regardless of whether they are housed at standard room temperature (22°C) or thermoneutrality (30°C).

For GLP-1 and hFGF21 drugs, the mouse model's housing temperature is less critical for predicting efficacy magnitude than for other drug classes. These drugs work robustly in both cold-stressed and thermoneutral environments.

GDF15 analogs are significantly more effective at inducing weight loss in mice housed at standard room temperature (22°C) compared to thermoneutrality (30°C), with efficacy dropping by half at higher temperatures.

If developing GDF15-based therapies, preclinical data from cold-housed mice may overestimate efficacy compared to thermoneutral conditions. The drug's effectiveness is halved when mice are not cold-stressed.

Peptide YY (PYY) analogs show greater weight loss efficacy in mice housed at thermoneutrality (30°C) compared to standard room temperature (22°C), contrary to the trend seen with GDF15.

For PYY-based therapies, preclinical data from thermoneutral mice may better reflect potential efficacy than data from cold-stressed mice, where the drug appears largely ineffective.

Semaglutide treatment for type 2 diabetes does not directly cause retinal damage; observed early worsening of diabetic retinopathy is primarily driven by the magnitude and speed of HbA1c reduction rather than the drug itself.

If you have type 2 diabetes and are starting semaglutide, do not avoid it out of fear of blindness. The risk of retinopathy worsening is linked to how fast your blood sugar drops, not the drug itself. To stay safe, your doctor should check your eyes before starting, and may reduce your insulin or sulfonylurea dose to prevent a rapid glucose drop. Regular eye exams are essential.

Bariatric surgery significantly reduces all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) compared to medical therapy in patients with severe obesity and Type 2 Diabetes.

For severe obesity and Type 2 Diabetes, bariatric surgery is the most effective treatment for reducing heart disease risk and death. It significantly lowers the risk of heart attack, stroke, and heart failure compared to medical therapy alone. Discuss surgical options with a specialist if lifestyle changes and medications are insufficient.

SGLT2 inhibitors reduce cardiovascular mortality and heart failure hospitalization in insulin-resistant patients by promoting ketone body production and reducing sympathetic overdrive.

If you have Type 2 Diabetes and heart issues, ask your doctor about SGLT2 inhibitors (like Jardiance or Farxiga). They are proven to protect your heart and reduce hospital stays, not just lower blood sugar. The benefit comes from how they change your heart's energy use and stress levels.

GLP-1 receptor agonists reduce major adverse cardiac events and cardiovascular mortality in patients with Type 2 Diabetes, particularly those without pre-existing heart failure.

If you have Type 2 Diabetes, GLP-1 drugs (like Ozempic or Victoza) are highly recommended for heart protection. They significantly lower the risk of heart attacks and death. If you already have heart failure, they still help prevent new cases but may not stop existing failure from worsening as effectively.

SGLT2 inhibitors lower blood glucose by inhibiting renal glucose reabsorption, resulting in glucosuria, with efficacy dependent on maintaining a filtered glucose load above 80g/day.

SGLT2 inhibitors are effective for lowering blood sugar by helping your kidneys excrete excess glucose, but they only work well if your blood sugar is high enough and your kidneys are functioning adequately. They also offer heart and kidney protection. You must take them as prescribed and maintain good hygiene to minimize infection risks.

Bariatric surgery is a highly effective therapeutic option for individuals with severe obesity (BMI ≥40 or ≥35 with comorbidities) that induces T2DM remission through metabolic changes beyond simple restriction.

If you have a BMI of 40 or higher (or 35+ with diabetes/liver disease), consult a specialist about bariatric surgery. It is a proven, durable treatment that can reverse diabetes through hormonal changes, not just weight loss, but requires lifelong medical monitoring.

GLP-1 receptor agonists (e.g., semaglutide, liraglutide) improve MASH resolution but do not significantly improve liver fibrosis in patients with compensated cirrhosis.

Semaglutide (2.4mg weekly) helps resolve MASH but does not reverse fibrosis in patients with cirrhosis. It is effective for weight loss and glucose control but should not be relied upon to fix advanced scarring alone.

Smoking and consumption of goitrogenic foods (specifically cruciferous vegetables and processed meats) increase urinary levels of thiocyanate and nitrate, which act as competitive inhibitors of iodine uptake, thereby increasing the risk of iodine deficiency.

Smokers and those eating large amounts of cruciferous vegetables (broccoli, cabbage) or processed meats may have higher levels of goitrogens (thiocyanate/nitrate) in their urine. These substances compete with iodine for absorption. If you smoke or eat these foods heavily, ensure your iodine intake is adequate through diet or supplements to counteract this inhibition.

Pharmacological activation of G protein-coupled receptors (GPCRs) in thermogenic brown and beige adipocytes can increase energy expenditure and improve metabolic health, but current adrenergic agonists have a narrow safety window due to cardiovascular side effects.

While cold exposure is a natural way to activate brown fat, scientists are developing drugs that target specific receptors (GPCRs) to do the same thing. Current drugs like mirabegron show promise for boosting metabolism by ~200 kcal/day, but they can affect heart rate. Future treatments aim to target these receptors more selectively to avoid side effects while still improving metabolic health.

Non-adrenergic Gs-coupled receptors (e.g., secretin, glucagon, adenosine) can stimulate brown adipose tissue thermogenesis independently of the sympathetic nervous system, offering a potential pathway to avoid cardiovascular side effects associated with adrenergic agonists.

Scientists are exploring hormones other than adrenaline (like secretin or glucagon) to activate fat-burning cells. These hormones can boost glucose uptake in brown fat by 57%, but they break down quickly. Future drugs may modify these hormones to last longer, potentially offering a way to boost metabolism without the heart risks of current adrenaline-targeting drugs.

Resmetirom, a selective thyroid hormone receptor beta (THR-β) agonist, significantly reduces hepatic fat content and improves fibrosis markers in patients with non-cirrhotic MASH.

If you have MASH (formerly NASH) with significant liver fat, ask your doctor about resmetirom. It is an FDA-approved medication that targets the liver specifically to reduce fat and improve fibrosis. The standard dose is 80mg or 100mg taken once daily. It is not a supplement but a prescription drug with specific eligibility criteria (non-cirrhotic MASH).

Postprandial plasma leucine concentration and ingested leucine dose are poor predictors of muscle protein synthesis (MPS) rates when protein is consumed as whole foods or mixed meals, indicating that leucine is not the sole or primary driver of the anabolic response in complex nutritional contexts.

Stop obsessing over hitting specific leucine targets with isolated powders. When you eat whole protein sources like eggs, meat, or dairy, your body handles the anabolic signaling effectively regardless of minor variations in leucine content. The food matrix and other nutrients play a crucial role that isolated leucine metrics miss.

GLP-1 receptor agonists provide cardiovascular protection through peripheral anti-inflammatory effects, independent of their weight-loss or glucose-lowering actions.

Beyond helping you lose weight, GLP-1 medications like semaglutide have been shown to protect your heart. This protection comes from reducing inflammation in your body's peripheral tissues, offering a dual benefit for metabolic and cardiovascular health.

Pegozafermin (BIO89-100), an FGF-21 analog, demonstrates improvement in liver fibrosis in patients with MASH, as shown in Phase 2b trials, and has entered Phase 3 clinical trials.

Pegozafermin is an experimental drug for MASH that works by mimicking FGF-21. It is given as a subcutaneous injection every two weeks. It is currently in Phase 3 trials and not yet approved.

Pioglitazone, a PPAR-gamma agonist, improves steatosis, inflammation, and liver biomarkers in patients with MAFLD, but its effect on liver fibrosis is not clear.

Pioglitazone is an older diabetes drug that can improve liver fat and inflammation in MAFLD patients. However, it may cause weight gain and other side effects, and its ability to reverse liver scarring is unclear. It is sometimes used in patients with T2DM and MASH.

Chronic administration of GIP receptor agonists (specifically GIP108) causes functional desensitization of the GIP receptor in pancreatic islets, reducing the efficacy of subsequent glucose-lowering challenges.

Long-term use of GIP-based therapies (like tirzepatide) triggers a biological adaptation where the pancreas becomes less responsive to the drug's glucose-lowering signal. This is a known mechanism called desensitization. However, the drug still promotes weight loss, suggesting the benefit comes from multiple pathways, not just pancreatic sensitivity. If glycemic control wanes, dose adjustments may be necessary.

While a protein-polyphenol beverage accelerates early functional adaptations and increases type II fiber hypertrophy, it does not further increase peak isometric torque, overall muscle function, or total quadriceps muscle volume compared to placebo in the later stages of resistance training (sessions 10-30).

Don't expect this specific supplement to make you bigger or stronger than standard protein in the long run. The early boost in function and fiber size is nice, but for overall muscle volume and peak strength after the first month, it offers no advantage over a placebo or standard protein. You can likely stop the specialized polyphenol supplements after the initial adaptation phase.

Iso-caloric substitution of poly-unsaturated fat for saturated fat is associated with an increased risk of cancer-related mortality.

If you are replacing saturated fats (e.g., from butter, cheese, or red meat) with poly-unsaturated fats (e.g., from vegetable oils, nuts, or fish), this study suggests your risk of dying from cancer may increase by 12%. Consider balancing your fat intake and not relying solely on PUFA-rich oils as a health strategy.

Polygenic scores derived from 59 SNPs associated with central adiposity predict a smaller reduction in waist circumference after one year of lifestyle intervention, though the effect size is too small to be clinically significant.

Your genes might make it slightly harder to lose belly fat compared to someone else with different genetics, but the difference is less than a centimeter. This is too small to matter for your health goals. Focus on the lifestyle intervention (diet and exercise) as it provides a much larger benefit than any genetic disadvantage.