Browse the evidence

Dietary macronutrient composition (low-carbohydrate vs. low-fat) does not explain differences in ad libitum energy intake because the resulting changes in gut-derived appetite hormones (GLP-1, GIP, PYY, ghrelin) are insufficient to override other dietary factors like energy density and hyper-palatability.

Don't rely on low-carb or low-fat diets to magically regulate your hunger through hormones. This study shows that even when hormones change significantly, they don't dictate how much you eat if other factors like energy density and taste are present. Focus on the physical properties of food (volume, density) rather than just the macronutrient ratio for short-term intake control.

GLP-1 administration (25 nmol/kg) significantly augments glucose-stimulated insulin secretion and improves glucose tolerance in mice, whereas GLP-2 (25 nmol/kg) improves glucose tolerance without directly augmenting insulin secretion.

Both GLP-1 and GLP-2 peptides improve blood glucose levels in mice, but they do so through different biological pathways. GLP-1 works by telling beta cells to release more insulin, while GLP-2 improves glucose handling without directly increasing insulin secretion. This suggests that targeting GLP-2 receptors could be a viable strategy for glucose control that avoids potential side effects of excessive insulin secretion.

Both GLP-1 and GLP-2 suppress appetite and reduce food intake in mice, regardless of their differential effects on insulin secretion.

Both GLP-1 and GLP-2 peptides reduce food intake in mice, suggesting that GLP-2 could be used to manage appetite without necessarily stimulating insulin secretion. This makes GLP-2 a potential candidate for obesity treatment where insulin secretion is not desired.

Both GLP-1 and GLP-2 promote beta-cell proliferation and protect against cytokine-induced apoptosis, preserving beta-cell mass and function.

Both GLP-1 and GLP-2 help protect beta-cells from death and promote their growth. This suggests that GLP-2 could be used to preserve beta-cell mass in diabetes, potentially slowing disease progression.

Naltrexone/Bupropion is not recommended for individuals with obesity and established atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF) due to potential hemodynamic stress and lack of outcome data.

If you have obesity and established heart disease or heart failure, naltrexone/bupropion is not recommended because it can increase heart rate and blood pressure, potentially worsening your condition. Safer, proven alternatives are available.

Semaglutide, despite achieving NASH resolution, failed to improve fibrosis stage in phase 2 trials, highlighting a gap in treating advanced fibrosis compared to resmetirom.

Semaglutide helps resolve NASH but does not improve fibrosis. Patients with advanced fibrosis should consider other options like resmetirom.

Obeticholic acid (OCA) trials for NASH were discontinued due to safety concerns and modest efficacy, despite showing some histological improvement.

Obeticholic acid is not approved for NASH due to safety issues.

Lixisenatide and high-dose efpeglenatide (6 mg/week) are associated with a statistically significant increase in hearing loss events compared to controls, whereas other GLP-1 receptor agonists and SGLT2 inhibitors do not demonstrate this elevated risk.

If you are taking Lixisenatide or high-dose Efpeglenatide, be aware of a potential increased risk of hearing loss. This risk is not seen with other GLP-1 drugs like Semaglutide or Dulaglutide in this analysis. Report any sudden hearing changes to your doctor immediately, but do not stop your medication without consulting them, as the absolute risk (NHH ~757) is relatively low.

Current NuSH trials rarely assess bone health, despite the known risk of bone mass reduction associated with significant weight loss.

If you are on NuSHs, ask your doctor about bone density scans, especially if you are post-menopausal or elderly. Ensure adequate calcium and vitamin D intake, as weight loss can compromise bone strength.

Biological mechanisms, specifically a defended weight set point driven by genetic and epigenetic factors, actively oppose weight loss maintenance by altering hunger hormones and reducing energy expenditure, making long-term weight loss difficult without continuous intervention.

Accept that maintaining weight loss is biologically harder than losing it due to hormonal defenses. Do not rely on short-term diets; instead, focus on long-term strategies like preventing 'weight creep' (0.5-1kg/year gain) through low-intensity lifestyle changes or considering long-term pharmacological support (like GLP-1 agonists or metformin) if indicated, rather than expecting a one-time fix.

Protein restriction (specifically low-protein, high-carbohydrate diets) extends lifespan and improves metabolic health in model organisms, likely through mechanisms distinct from or overlapping with calorie restriction, such as elevated FGF21.

In model organisms, restricting protein (while keeping calories normal) extends lifespan and improves metabolic health, partly by boosting FGF21. However, this comes at the cost of muscle mass. For humans, high protein is generally recommended for muscle maintenance, but excessive intake might increase mortality risk. The optimal protein intake likely balances longevity benefits with the need to preserve physical resilience, suggesting a moderate approach rather than extreme restriction or excess.

Activation of Glucagon-Like Peptide-1 Receptors (GLP-1R) in the Gustatory Cortex (GC) reduces homeostatic food intake in mice.

This research identifies a specific brain region (Gustatory Cortex) where GLP-1 receptors are active and influence how much we eat. While this doesn't change current dietary advice, it explains part of the mechanism behind GLP-1 based weight loss drugs, suggesting they work by altering how the brain processes taste and hunger signals, not just by signaling fullness from the gut.

The effect of GC GLP-1R activation on food intake is conditional on the palatability and fat content of the food, particularly in mice chronically maintained on a high-fat diet.

If you are trying to lose weight, switching from a high-fat diet to a lower-fat diet might make appetite-suppressing medications (like GLP-1 agonists) more effective. The brain's response to these drugs seems to depend on the palatability of the food, and changing your diet may help reset these signals.

GIPR agonism in humans may not provide weight loss benefits and can negate the appetite-suppressing effects of GLP-1.

While GIPR agonists work in animals, human studies show that adding GIP to GLP-1 can actually stop GLP-1 from working as well for appetite control. This suggests the human body responds differently than mice.

DPP-4 inhibitors (specifically Saxagliptin and Alogliptin) may increase the risk of hospitalization for heart failure, whereas Sitagliptin and Linagliptin appear neutral.

If you have Type 2 Diabetes and Heart Failure, be cautious with DPP-4 inhibitors. Saxagliptin and Alogliptin have been linked to an increased risk of heart failure hospitalization. However, Sitagliptin and Linagliptin have shown neutral effects. Discuss the specific risks and benefits with your doctor to choose the safest option for your heart.

GLP1R-expressing neurons in the human hypothalamus, specifically those co-expressing POMC in the arcuate nucleus and AVP in the paraventricular/supraoptic nuclei, are the primary neural targets mediating the appetite-suppressing effects of GLP-1 receptor agonists like semaglutide.

If you are using a GLP-1 medication like semaglutide, its ability to reduce your appetite is biologically grounded in its action on specific neurons in your hypothalamus (brain). This confirms that the reduction in food intake is a direct neurological effect, not just a side effect of slower digestion.

GIPR (Gastric Inhibitory Polypeptide Receptor) is expressed in human hypothalamic ependymal cells surrounding the third ventricle, suggesting a potential mechanism for how GIPR-targeting drugs like tirzepatide access the brain.

This research suggests that drugs targeting the GIP receptor (like tirzepatide) may interact with cells lining the fluid spaces in your brain. This provides a biological basis for how these medications might influence brain function related to appetite, beyond just their effects on the stomach.

Rare deleterious variants in the gene CORO1A are significantly associated with changes in BMI at the population level, identifying it as a novel genetic factor in obesity risk.

Genetic testing may reveal variants in the CORO1A gene that predispose individuals to higher BMI. This is a newly identified genetic risk factor.

Second-generation oral contraceptive pill phase (active vs. inactive) does not influence muscle protein synthesis or myofibrillar proteolysis at rest or in response to resistance exercise.

If you take second-generation birth control pills, you can train for muscle growth without worrying about your pill cycle. Your muscles build and break down protein at the same rate whether you are on the active pills or the placebo week. Focus on your training and nutrition; the pill phase does not matter for your results.

Adding the long-acting PYY3-36 analogue PYY1875 (1.0 mg/week) to semaglutide (2.4 mg/week) yields only modest, non-clinically meaningful additional weight loss in people with obesity and is poorly tolerated due to gastrointestinal adverse events.

For individuals already on semaglutide, adding PYY1875 at 1.0 mg weekly provides only a small, likely unnoticeable additional weight loss benefit while significantly increasing the risk of gastrointestinal side effects like nausea. The 2.0 mg dose was not tolerated. Current evidence suggests this combination is not a viable strategy for improving weight loss outcomes due to poor tolerability and lack of clinical significance.

Endogenous peripheral GLP-1 enhances glucose-induced insulin release primarily through a vago-vagal reflex mediated by GLP-1 receptors on vagal sensory fibers, rather than through direct endocrine action on pancreatic beta-cells.

Your body's natural response to eating involves a complex gut-brain-heart axis. GLP-1 released from your gut doesn't just float to your pancreas; it signals your vagus nerve to help manage insulin. This highlights the importance of the neural connection between digestion and metabolic control, suggesting that factors affecting nerve health or gut signaling might influence metabolic efficiency.

Central GLP-1 produced by hindbrain PPG neurons and peripheral GLP-1 from intestinal L-cells regulate food intake through independent pathways, rather than acting synergistically or additively.

Your body uses two separate GLP-1 systems—one in your gut and one in your brainstem—to control hunger. They don't necessarily rely on each other. This means issues with gut hormone production might not directly impair your brain's satiety signals, and vice versa.

Physiological levels of GIP promote fat accumulation and insulin resistance in the context of high-fat diets and aging, acting as a 'thrifty hormone' that stores nutrients.

In the context of a high-fat diet, your body's natural GIP hormone helps store fat and may contribute to insulin resistance. This is why blocking GIP (antagonism) can help reduce obesity, while stimulating it pharmacologically (agonism) works through different mechanisms like appetite suppression in the brain.

Utilization of newer non-insulin glucose-lowering drugs (SGLT2 inhibitors and GLP-1RAs) has increased significantly in Australia, driven by cardiovascular and renal benefits, while older agents (sulphonylureas, glitazones) have declined.

If you have Type 2 Diabetes, talk to your doctor about newer medications like SGLT2 inhibitors or GLP-1RAs. These drugs not only lower blood sugar but also protect your heart and kidneys. While they are more expensive than older medications, they are increasingly recommended as first-line treatments due to these additional benefits.