Browse the evidence

Gut peptides such as GLP-1 and PYY, along with vagal afferent signaling, play a critical role in homeostatic appetite suppression and satiety signaling.

Your gut produces hormones like GLP-1 and PYY when you eat, which signal your brain to stop eating. This is a natural biological process. Understanding this can help explain why certain foods or eating patterns might affect your satiety levels.

Adipocyte ATP-citrate lyase (ACLY) is essential for handling dietary carbohydrates and maintaining metabolic homeostasis in females, as its deficiency leads to lipodystrophy-like phenotypes, hepatic steatosis, and insulin resistance when consuming high-carbohydrate diets.

For women, high-carbohydrate diets may pose a higher metabolic risk if adipose tissue function is compromised, potentially leading to fat storage in the liver and insulin resistance. Men may tolerate similar carbohydrate loads better. This suggests that women might benefit from monitoring carbohydrate quality and quantity more closely, especially if they have underlying metabolic vulnerabilities.

Brainstem cholecystokinin-expressing (CCKAP/NTS) neurons are required for the appetite-suppressing and body-weight-lowering effects of GLP-1 receptor agonists.

GLP-1 medications like semaglutide or liraglutide work by activating specific neurons in the brainstem (CCK neurons). If these neurons are blocked or non-functional, the medication will not suppress appetite or reduce body weight. This highlights that the drug's efficacy depends on this specific neural pathway.

GIP receptor activation reduces the recruitment of CCKAP/NTS neurons and selectively reduces conditioned taste avoidance without abolishing weight loss.

Adding GIP receptor activation to GLP-1 therapy reduces the activation of brainstem neurons responsible for nausea, thereby reducing side effects like nausea without significantly compromising the weight-loss benefits. This suggests dual-agonists may offer a better tolerability profile.

BMI is an imperfect individual predictor of obesity-related risk because metabolically healthy individuals with high BMI may still have elevated cardiovascular risk and mortality compared to normal-weight individuals.

Even if your blood sugar and cholesterol are normal, carrying excess weight (BMI ≥ 30) still increases your risk of heart problems and early death compared to being a normal weight. You should still aim for weight loss to reduce this residual risk.

Higher intake of unprocessed red meat and total meat is associated with a significantly higher incidence of atherosclerotic cardiovascular disease (ASCVD) in older adults, partly mediated by gut microbiota-derived metabolites TMAO, gamma-butyrobetaine, and crotonobetaine.

If you are over 65, be mindful of your red meat consumption. This study links higher intake of unprocessed red meat and total meat to a higher risk of heart disease and stroke. The risk is partly explained by how gut bacteria process compounds in red meat into substances like TMAO. You don't need to eliminate red meat entirely, but balancing it with fish, poultry, and plant-based proteins may help lower your cardiovascular risk.

Resistance training induces 'anabolic resistance' in older adults, characterized by lower muscle protein synthesis rates in response to protein feeding and exercise compared to younger individuals.

Older adults experience 'anabolic resistance,' meaning their muscles respond less strongly to protein and exercise than younger people's. To overcome this, older adults may need higher protein intakes and more consistent resistance training to stimulate muscle growth.

Co-ingesting 10g of citrulline with 15g of whey protein does not enhance myofibrillar protein synthesis (MPS) or blood flow in elderly men compared to 15g of whey protein alone, despite increasing arginine levels.

For elderly men, adding 10g of citrulline to a small dose of protein (15g) after exercise does not boost muscle building or blood flow any more than the protein alone. To maximize muscle protein synthesis, consume a larger dose of high-quality protein (like 45g of whey) instead of relying on citrulline to make a small dose work better.

Chronic high-fat diet consumption increases the formation and activation of mTOR complexes 1 and 2 in skeletal muscle, leading to insulin resistance via S6K1-mediated inhibition of IRS1, whereas exercise training reverses this process by enhancing AMPK activation.

Chronic overconsumption of fats can trigger molecular switches (mTOR) in your muscles that block insulin, leading to resistance. Regular exercise acts as a counter-switch by activating AMPK, which turns off mTOR and restores insulin sensitivity. To maintain metabolic health, balance fat intake with consistent physical activity.

Activation of AMPK by AICAR abolishes lipid-induced mTOR activation in vitro, confirming that AMPK activation is sufficient to reverse the negative effects of high lipid availability on insulin signaling.

AMPK activation, naturally triggered by exercise, directly inhibits the mTOR pathway which is overactivated by high fat intake. This suggests that boosting AMPK activity (via exercise) is a direct way to counteract the metabolic effects of a high-fat diet.

In older adults, obesity and low HDL cholesterol significantly increase the risk of type 2 diabetes preceded by insulin resistance, but are associated with a lower risk of diabetes preceded by beta-cell dysfunction.

For older adults, high body weight and low HDL cholesterol are strong predictors for developing diabetes driven by insulin resistance, but may actually be associated with a lower risk of diabetes driven by beta-cell failure. This suggests that metabolic subtyping is important for risk assessment in the elderly.

In older adults, higher age, greater adiposity, higher systolic blood pressure, lower HDL, and higher triglycerides are independently associated with greater insulin resistance but better beta-cell function.

In older adults, traditional cardiovascular risk factors like high blood pressure and high triglycerides correlate with higher insulin resistance but are paradoxically associated with better preserved beta-cell function.

Intensive glucose-lowering strategies significantly increase the risk of severe hypoglycemia compared to standard therapy.

If you are on intensive diabetes treatment to lower your blood sugar significantly, be aware that your risk of severe low blood sugar (hypoglycemia) nearly doubles compared to standard treatment. This risk must be weighed against the benefits for your eyes and kidneys. Regular monitoring and awareness of hypoglycemia symptoms are crucial.

Pioglitazone improves NASH histology without worsening fibrosis in patients with T2DM and MAFLD, but its use is limited by side effects including weight gain, fluid retention, and potential bladder cancer risk.

Pioglitazone (45mg daily) can improve liver inflammation (NASH) in people with type 2 diabetes and fatty liver without worsening scarring. However, it can cause weight gain, fluid retention, and may increase the risk of bladder cancer in some people. It is not recommended for everyone and should be used with caution, especially if you have a history of heart failure or bladder cancer.

Bariatric surgery (specifically Roux-en-Y gastric bypass) induces durable weight loss and type 2 diabetes remission through mechanisms beyond simple caloric restriction, including blunted metabolic adaptation, altered gut hormone secretion (increased GLP-1, PYY), and changes in food preference/hedonics.

Bariatric surgery works by changing gut hormones and metabolism, not just by making the stomach smaller. This insight drives the development of non-surgical drugs (like GLP-1 agonists) that mimic these hormonal changes to help with weight loss and diabetes without surgery.

Bariatric surgery improves glucose homeostasis and insulin sensitivity through mechanisms involving increased gut hormone secretion (GLP-1, PYY) and altered bile acid metabolism, independent of weight loss in some models.

Surgery improves blood sugar control not just by weight loss, but by changing how your gut hormones and bile acids work. This can lead to diabetes remission even before significant weight loss occurs.

Obesity accelerates biological cardiovascular ageing by inducing structural and functional cardiac and vascular changes that mimic those of chronological ageing, independent of traditional risk factors.

Your heart ages based on how you treat it, not just your birth year. Obesity forces your heart to work harder and remodels it to look and function like an older, non-obese heart. Losing weight can reverse these changes, effectively turning back the biological clock of your cardiovascular system.

Central nervous system (CNS) activation of the Glucose-dependent Insulinotropic Polypeptide Receptor (GIPR) is required for the synergistic weight loss observed with dual GIPR/GLP-1R agonists.

If you are using a GLP-1 medication for weight loss or diabetes and struggle with side effects or plateauing results, newer dual-acting medications (targeting both GIP and GLP-1 receptors) may offer better weight loss with potentially fewer gastrointestinal side effects. This is because these drugs work on brain pathways that suppress appetite and may reduce the nausea often caused by older GLP-1-only drugs. Consult your doctor about whether a dual-agonist is appropriate for your metabolic health.

Liraglutide-induced weight loss is significantly attenuated in individuals consuming high-carbohydrate diets when hepatic FGF21 signaling is absent, indicating that FGF21 mediates the appetite-suppressing effects of GLP-1 receptor agonists specifically in the context of high carbohydrate intake.

If you are using a GLP-1 receptor agonist like liraglutide, your weight loss results may be suboptimal if you consume a high-carbohydrate diet. This is because the drug relies on a hormone called FGF21 to help suppress appetite, and this hormone is most effective at reducing food intake when carbohydrates are present. To maximize weight loss, consider reducing your carbohydrate intake, as this may enhance the drug's ability to engage the FGF21 pathway and promote greater weight reduction.

The rs3758391 C/T single-nucleotide polymorphism in the human SIRT1 promoter determines the magnitude of SIRT1 upregulation in skeletal muscle during long-term calorie restriction, with the T allele facilitating greater expression than the C allele.

If you are following a calorie-restricted diet, your genetic variant rs3758391 in the SIRT1 gene influences how much your muscle's SIRT1 levels rise. Individuals with the T allele (CT or TT genotypes) experience a significantly larger increase in SIRT1 expression after 6 months of restriction compared to those with the CC genotype. This does not mean CC individuals fail to adapt, but their molecular response is blunted. This effect is not seen after only 3 months of restriction, suggesting robust, long-term caloric deficit is required to observe these genetic differences.

In non-obese adult humans, circulating leptin levels do not predict or influence adaptive variations in energy expenditure (resting metabolic rate, thermic effect of feeding, or total energy expenditure).

For healthy, non-obese adults, your circulating leptin levels do not dictate your metabolic rate or how many calories you burn through activity. Focus on maintaining muscle mass and physical activity, as these are the primary drivers of energy expenditure, rather than trying to manipulate leptin levels directly.

GLP-1R signaling primarily occurs through the Gαs/cAMP pathway, leading to insulin secretion, but also involves Gαq and β-arrestin pathways which contribute to receptor internalization and other metabolic effects.

GLP-1 drugs work by activating specific pathways in the body. The main pathway increases insulin when blood sugar is high. Other pathways help with receptor recycling and may contribute to other effects like cell survival.

Non-POMC neurons, specifically GABAergic neurons, mediate leptin's direct effects on energy balance and food intake, influencing POMC neurons indirectly.

This suggests that treatments targeting only POMC neurons may fail to reduce appetite. Future therapies might need to target GABAergic neurons or other non-POMC pathways to effectively manage obesity via leptin signaling.

POMC neurons expressing the glucagon-like peptide 1 receptor (Glp1r) are a distinct subpopulation from those expressing the leptin receptor (Lepr), and Glp1r-expressing POMC neurons may regulate energy balance.

This heterogeneity explains why broad activation of POMC neurons might have mixed results. Targeted therapies might need to distinguish between Lepr-expressing (glucose) and Glp1r-expressing (energy balance) subsets.