Revisiting Fire in a Bottle: Physiological Insulin Resistance

Below I am going to be listing blog pages from Brad which inspired and intrigued me about this work. I wanted to put these pages and some dot point summaries of them together to make for myself a simple reminder guide to his work and evidently the work of Petro Dobromylskyj. The dot points were generated with ChatGPT because I struggle to put thought into words and this was more time efficient. I have read over and cross referenced them with the original articles to agree with the summaries.

Physiological Insulin Resistance: https://fireinabottle.net/physiological-insulin-resistance/

• After a starchy meal: blood glucose rises → insulin is released → insulin binds to receptors on muscle/fat cells → GLUT4 transporters move to membrane → cells take up glucose.

• In muscle: glucose is used to refill glycogen stores. In fat tissue: lipolysis (free-fatty‐acid release) is suppressed and instead glucose may be used for making fat (de novo lipogenesis).

• Over time, as the cell’s mitochondria generate ATP, the proton gradient across the inner mitochondrial membrane increases. Eventually the gradient becomes so high that electrons struggle to flow freely through the electron transport chain.

• That leads to increased production of reactive oxygen species (ROS) — superoxide → hydrogen peroxide. These ROS migrate out of mitochondria and inhibit insulin signalling in the cell.

• The inhibition of insulin signalling in that context is termed “physiological insulin resistance” — a normal, cell-level mechanism for stopping further glucose uptake when the cell is already “full.”

• The article emphasises that this is not the same as pathological insulin resistance (as in metabolic syndrome) — it is a transient, natural switch: when mitochondria are saturated (high ATP, high gradient, high ROS), the cell becomes less insulin sensitive; when ATP is used up (ADP rises), the gradient drops, ROS production falls, and insulin sensitivity returns.

• The author credits Peter at Hyperlipid (blogger of “Hyperlipid”) as inspiration for much of the idea, and mentions that the concept is built into the “ROS Theory of Obesity.”

• The key takeaway: physiological insulin resistance acts like a cell’s internal “dinner-table” rule — once “full”, it says “thanks, I’ll stop taking more glucose for now.”

This is what fat burning looks like: https://fireinabottle.net/this-is-what-fat-burning-looks-like/

• The post discusses a study where people ate a low-fat vegan diet for two days, then consumed a shake with 24 g stearic acid.

• Before the stearic acid, their mitochondria were fragmented — interpreted as a low fat-burning state.

• Within ~3 hours of consuming stearic acid, mitochondria fused into long chains — interpreted as a shift into fat-burning mode.

• A blood marker for fat oxidation (acylcarnitine) dropped after the shake, used as evidence that cells switched to burning fat.

• The author links this to their “ROS Theory of Obesity,” saying saturated fat triggers physiological insulin resistance that keeps cells using fat for fuel.

• The core idea: mitochondrial shape changes quickly in response to diet and may visually represent the metabolic shift into fat-burning.

Saturated Fat Causes Physiological Insulin Resistance in Humans: https://fireinabottle.net/saturated-fat-causes-physiological-insulin-resistance-in-humans/

• The article presents the concept of physiological insulin resistance (PIR) — a short-term, reversible insulin-resistant state triggered when cells oxidise saturated fat.

• The author argues that when long-chain saturated fatty acids (SFA) are oxidised in mitochondria, they generate excess reactive oxygen species (ROS) which inhibit insulin signalling — thus causing PIR.

• A referenced human study: participants followed a high saturated fat diet for 24 hours versus a high carbohydrate diet; the SFA group showed higher blood glucose during an insulin suppression test, indicating insulin resistance.

• Importantly, the author emphasises this is not pathological insulin resistance (as seen in type 2 diabetes) but a transient, adaptive state: “Insulin resistance persisted overnight … and was attenuated by one day on a healthy diet.”

• From the author’s framework: In the SFA condition, fat cells become less responsive to insulin (i.e., reduced glucose uptake/storage) so they continue burning fatty acids rather than switching to glucose.

• The article thus positions the consumption of saturated fat as a regulator of metabolic flexibility: by inducing a temporary insulin‐resistant state, tissues remain in fat-oxidising mode rather than rapidly switching to glucose when insulin rises.

Unsaturated Fat Prevents Physiological Insulin Resistance in Humans: https://fireinabottle.net/unsaturated-fat-prevents-physiological-insulin-resistance-in-humans/

• The article describes a human study comparing two ketogenic diets: one high in saturated fat (SFA) and one high in poly-unsaturated fat (PUFA, e.g., soybean oil).

• In the high-saturated fat group, participants developed what the author calls physiological insulin resistance (PIR) — a reversible, adaptive insulin-resistant state linked to fat oxidation rather than glucose metabolism.

• In contrast, the high-unsaturated fat (mostly PUFA) group did not show PIR, despite being on a similar ketogenic (very low-carbohydrate) diet.

• Mechanistic explanation offered: saturated fats generate more FADH₂ during oxidation, which overloads the mitochondrial electron transport chain (especially Coenzyme Q), increasing reactive oxygen species (ROS) like superoxide/hydrogen peroxide — these ROS act as signals that suppress insulin signalling.

• By contrast, unsaturated fats (with more double-bonds) produce less FADH₂ per unit oxidised, thus fewer electrons pass through the CoQ “bottleneck,” resulting in less ROS production, and therefore insulin signalling remains intact.

• The article uses this as evidence to support the author’s broader “ROS Theory of Obesity” framework: that mitochondrial ROS serve as a metabolic signal toggling between glucose vs fat fuel use, and that fat type influences that switch.

The Amount of Polyunsaturated fat in the Modern American Diet Fattens up Mice Without Additional Calories: https://fireinabottle.net/the-amount-of-polyunsaturated-fat-in-the-modern-american-diet-fattens-up-mice-without-additional-calories/

• The post reviews a mouse‐study in which two groups of mice were fed diets that differed only in the proportion of linoleic acid (an omega-6 polyunsaturated fatty acid, PUFA) replacing saturated fat: one diet had ~1% of calories from linoleic acid; another had ~8%.

• Both groups consumed the same total calories; dietary fat content (%) (35% vs 60% fat) also didn’t meaningfully change fatness as long as the bulk was saturated fat—i.e., fatness tracked with linoleic acid proportion, not total fat.

• Result: the mice with the higher linoleic acid (~8% of calories) became significantly fatter than the mice with ~1% linoleic acid—despite equal calorie intake.

• The author uses this finding to argue that increasing levels of dietary linoleic acid (which approximate typical modern US intake) may promote fat storage by disrupting metabolic/fuel-use dynamics. He states the average American diet now provides ~8% of calories as linoleic acid—matching the fatter mice.

• Mechanistically, in the author’s model (the “ROS Theory of Obesity”), higher PUFA intake means less production of reactive oxygen species (ROS) via saturated-fat oxidation, which means less “physiological insulin resistance” (PIR) in fat cells, so fat cells continue storing rather than staying in fat-burning mode. (Though this theory is more implied than directly tested in the mouse study.)

• The study is framed as controlled (good quality for diet manipulation) but the author notes caveats: the mice strain used (C57BL/6j) is predisposed to gain weight on high‐fat diets and has known mitochondrial ETC defects, so the model may not fully translate to humans.

Long Chain Saturated Fat Causes Fat Loss in Mice: https://fireinabottle.net/long-chain-saturated-fat-causes-fat-loss-in-mice/

• Mice were fed either a typical chow diet, a diet high in the long-chain saturated fat stearic acid (~40% of calories, ~85% as stearic acid), or a diet high in unsaturated fat (40% calories) for 10 weeks.

• The mice on the stearic acid diet lost weight (or at least did not gain) over 10 weeks, while the chow and unsaturated‐fat groups gained weight.

• Fat mass: the stearic acid group lost around half their fat mass, compared with little change in the chow group and a fat mass increase in the unsaturated fat group.

• A second study (lower fat % diet) also found that the stearic acid fed mice consumed more calories yet had the lowest body fat and highest lean body mass among groups.

• The author links this to his “ROS Theory of Obesity”: the idea that oxidation of long-chain saturated fat produces more mitochondrial ROS, triggering “physiological insulin resistance” in adipocytes which prevents fat storage and keeps the body in fat-burning mode.

• The article makes clear this is an animal (mouse) model and emphasizes mechanistic hypotheses rather than direct human recommendations.

Butter Causes a High Level of Available Energy 8 Hours After a Meal: https://fireinabottle.net/butter-causes-a-high-level-of-available-energy-8-hours-after-a-meal/

• The author references a Spanish study in which participants consumed isocaloric high-fat meals (≈800 kcal, low carbohydrate ~160 kcal) differing by type of fat: butter (high saturated fat), olive oil, high-palmitic sunflower oil, or a fish/vegetable oil mix.

• After the meals, free fatty acids (FFAs) in the bloodstream dropped in all groups (due to insulin after the meal), reached a minimum at ~2 hours, then rebounded over time.

• In the butter (high saturated fat) group: by ~3 hours post-meal, FFAs had returned to pre-meal levels (indicating fat cells still releasing energy). In the other fat-type groups, FFAs remained lower for longer (less available energy) until ~4-5 hours.

• In the butter group, FFAs then climbed above pre-meal levels by ~4 hours and stayed elevated through the full 8-hour measurement period. The author interprets this as “extended energy availability” for tissues.

• Triglycerides (blood fats) also behaved differently: in the butter group the rise lasted ~5 hours, the fastest absorption rate, suggesting the fat was absorbed quickly and remained circulating longer rather than being stored immediately.

• The author’s interpretation: high saturated fat (butter) causes a state in which fat cells are relatively insulin resistant (i.e., less suppressed by insulin), meaning lipolysis (release of FFAs) is less inhibited. Thus, energy remains available from fat cells for longer, which may reduce hunger in the period 3-8 hours post-meal.