Browse the evidence

Thiazolidinediones and metformin are insulin-sensitizing pharmacological agents that can treat NAFLD by reducing insulin resistance in the liver and periphery, respectively.

If you have fatty liver, doctors may prescribe insulin-sensitizing drugs like metformin or thiazolidinediones to help reduce liver fat and improve metabolic health by targeting insulin resistance.

Adiponectin levels are negatively correlated with liver fat and hepatic insulin resistance, and low levels are associated with more extensive necroinflammation in NAFLD.

Higher levels of the hormone adiponectin are protective against fatty liver and inflammation. Low levels are a sign of worse liver disease and insulin resistance.

Endogenous oestrogens protect premenopausal women from type 2 diabetes by promoting subcutaneous fat storage, enhancing insulin sensitivity, and preserving beta-cell function, whereas the loss of oestrogen during menopause eliminates this protection and increases diabetes risk.

For women, maintaining metabolic health is heavily influenced by oestrogen levels. Before menopause, your body naturally stores fat in a safer (subcutaneous) way and stays more insulin-sensitive than men. After menopause, this protection fades, increasing diabetes risk. To counter this, focus on preserving muscle mass and managing visceral fat through exercise and diet, as these become more critical once oestrogen levels drop. Discuss hormone therapy options with your doctor if you are at high risk.

Oestrogen receptor alpha (ERα) activation mediates the protective effects of oestrogens on metabolic health by promoting insulin synthesis, beta-cell survival, and energy expenditure through brown adipose tissue beiging.

The protective benefits of oestrogen in women are largely driven by its interaction with specific receptors (ERα) in key metabolic organs. This interaction helps protect the pancreas, improves how muscles use insulin, and boosts energy burning in fat tissue. This highlights why maintaining hormonal balance is crucial for metabolic health.

Exogenous administration of FGF21 induces weight loss and improves glycemia in obese animal models primarily by increasing energy expenditure rather than reducing food intake.

FGF21 is a hormone that helps burn energy and manage blood sugar, but it does not work by making you hungry. In obese individuals, the body becomes resistant to its natural signals, but high-dose treatments can still be effective.

FGF21 promotes the browning of white adipose tissue (WAT) and increases thermogenesis in brown adipose tissue (BAT) in response to cold exposure and metabolic stress.

FGF21 helps your body burn calories by turning white fat into brown-like fat, especially when you are cold or stressed. This process increases energy expenditure without requiring you to exercise more.

Obesity induces an FGF21-resistant state characterized by reduced KLB expression in adipose tissue, impairing FGF21 signaling.

In obesity, your body produces more FGF21 but becomes resistant to it. This resistance can be overcome with high-dose treatments.

Acute interleukin-6 (IL-6) infusion enhances insulin-stimulated glucose disposal in healthy humans and increases glucose uptake and fatty acid oxidation in skeletal muscle cells via AMP-activated protein kinase (AMPK) activation.

Acute spikes in IL-6, such as those occurring during exercise, improve how your body handles insulin and burns fuel. This suggests that the inflammatory response to physical activity is a beneficial mechanism for metabolic health, rather than a harmful one. You do not need to suppress this acute signal to improve insulin sensitivity; it is part of the adaptive process.

Increased intramyocellular triglyceride (IMTG) content in insulin-sensitive skeletal muscle (soleus) is a primary determinant of in vivo whole-body insulin resistance in humans, independent of total body fat.

If you are lean but have a family history of type 2 diabetes, you may still have insulin resistance driven by fat stored inside your muscles, not just overall body weight. This internal muscle fat is a stronger predictor of metabolic health than your total body fat percentage. Regular physical activity helps manage this internal lipid storage.

High BMI acts as a protective factor against breast cancer in females aged 20 to under 50 years, a phenomenon potentially explained by the 'obesity paradox'.

While high BMI is generally harmful, this specific protective effect on breast cancer in younger women is complex and may be due to hormonal factors or methodological issues. It does not justify maintaining a high BMI, as the overall burden of disease from high BMI is substantial.

Short-chain fatty acids (SCFAs) produced by gut microbiota fermentation act as signaling molecules that regulate host energy metabolism, including stimulating leptin production, inhibiting gut motility via peptide YY, and regulating lipoprotein lipase activity through the suppression of fasting-induced adipocyte factor (Fiaf).

The byproducts of your gut bacteria (SCFAs) send signals to your brain and fat cells that regulate hunger and fat storage. Eating fiber-rich foods promotes the production of these SCFAs, which may help regulate appetite and fat deposition through complex hormonal pathways. This suggests that dietary fiber is not just about digestion but about hormonal signaling.

Pharmacological stimulation of GLP-1 receptors significantly reduces plasma glucose and improves glycaemic control in subjects with type 2 diabetes by preserving insulinotropic and glucagonostatic effects.

For individuals with type 2 diabetes, GLP-1 receptor agonists are a highly effective treatment option. They work by mimicking the natural hormone GLP-1 to lower blood sugar levels. This class of medication is a cornerstone of modern diabetes management due to its ability to improve glycaemic control.

Deiodinase activity is regulated by a variety of endogenous signaling molecules and xenobiotics, including hypoxia-inducible factor-1, growth factors, and bile acids.

Your thyroid hormone metabolism isn't just controlled by the thyroid gland; it's influenced by your body's response to stress, hypoxia, and other signals like growth factors and bile acids.

Dysregulation of AMPK activity is associated with insulin resistance and the metabolic syndrome in humans.

Maintaining a healthy weight and lifestyle can help keep your AMPK activity optimal, which is crucial for preventing insulin resistance and metabolic syndrome.

Increased intramyocellular lipid metabolites (fatty acyl CoAs and diacylglycerol) activate serine/threonine kinase cascades (e.g., PKC-theta), which phosphorylate IRS-1 on serine residues, thereby inhibiting insulin-stimulated glucose transport and causing skeletal muscle insulin resistance.

Insulin resistance in muscle is driven by specific lipid byproducts (like diacylglycerol) interfering with cell signaling, not just by having fat stores. Improving mitochondrial function and reducing these specific lipid intermediates can restore insulin sensitivity.

In the liver, increased diacylglycerol activates PKC-epsilon, which reduces IRS-2 tyrosine phosphorylation, leading to decreased glycogen synthase activation and increased gluconeogenesis, causing hepatic insulin resistance.

Hepatic insulin resistance is driven by lipid intermediates (DAG) interfering with liver insulin signaling, leading to excessive glucose production. Managing liver fat can improve this.

Knockdown of chemerin or its receptor CMKLR1 impairs adipocyte differentiation and reduces the expression of genes critical for glucose and lipid homeostasis.

This research highlights that chemerin is essential for healthy fat cell development and function. While not a direct intervention, it suggests that maintaining healthy adipokine levels may support metabolic health. No specific action is prescribed, but it underscores the importance of adipose tissue health in overall metabolism.

Down-regulation of hepatic Stearoyl-CoA Desaturase-1 (SCD-1) mediates a significant portion of leptin's metabolic effects, specifically by increasing energy expenditure and reducing hepatic lipid storage, independent of its anorectic effects.

This research highlights that metabolic health is driven by hormonal signaling, specifically the regulation of fat-processing enzymes like SCD-1. While this study was conducted on mice, it suggests that simply restricting calories may not be enough if hormonal pathways (like leptin resistance) are impaired. Strategies that improve hormonal sensitivity may be more effective for metabolic health than calorie restriction alone.

Activation of PPARγ by thiazolidinedione (TZD) drugs improves whole-body insulin sensitivity primarily by expanding subcutaneous adipose tissue capacity to sequester free fatty acids, thereby reducing lipotoxicity in skeletal muscle and liver.

If prescribed TZDs, understand that their benefit comes from helping your body store fat safely in the skin rather than letting it damage your liver and muscles. Monitor for swelling, as this is a known side effect linked to how the drug affects kidney sodium handling.

High body mass index (BMI) accelerates epigenetic aging of human liver tissue, independent of nonalcoholic fatty liver disease (NAFLD) severity, with an estimated increase of 2.7 years of epigenetic age for every 10-unit increase in BMI.

High BMI is associated with accelerated biological aging specifically in the liver, independent of fatty liver disease severity. This aging effect is not quickly reversed by weight loss, even after bariatric surgery, within the first 9 months. This suggests that maintaining a healthy weight is crucial for preventing long-term liver aging and associated risks like insulin resistance and liver cancer, and that weight loss efforts should be sustained long-term to potentially mitigate these epigenetic changes.

Beige fat cells are distinct from classical brown fat cells, originating from a different lineage (Myf5-negative) and characterized by low basal UCP1 expression that can be robustly activated by stimuli such as cold, exercise, or specific hormones.

Beige fat is a type of fat cell that can be 'turned on' within your white fat stores. Unlike brown fat, which is mostly present in infants, beige fat can be induced in adults through stimuli like cold exposure or exercise. This suggests that your existing fat stores have the potential to become metabolically active.

Blocking myostatin signaling prevents muscle wasting and induces hypertrophy in adult skeletal muscle.

Myostatin is a protein that limits muscle growth. Blocking it (experimentally via drugs or genetically) causes muscles to grow larger and prevents wasting. For natural training, understanding this helps explain why some people hit a 'genetic ceiling' on growth, as their myostatin levels may be higher.

Adiponectin is an insulin-sensitizing adipokine that improves glucose metabolism by activating AMPK and PPAR-α signaling pathways via AdipoR1 and AdipoR2 receptors, and its levels are inversely correlated with obesity and insulin resistance.

Your fat tissue acts as a hormone factory. In obesity, it produces less of the hormone adiponectin, which normally helps your muscles and liver use insulin. Restoring this signal, either through weight loss or future therapies, can improve insulin sensitivity.

Leptin resistance in obesity is characterized by high circulating leptin levels but a failure of the brain to respond, primarily due to impaired transport across the blood-brain barrier and reduced signaling, leading to continued food intake and insulin resistance.

In obesity, your body produces plenty of leptin, the hormone that tells your brain to stop eating, but your brain stops listening. This 'leptin resistance' is partly due to transport issues across the blood-brain barrier. Restoring sensitivity is key, not just adding more hormone.