Leptin

Leptin is a peptide hormone produced by fat cells that Ray Peat consistently identified as a central component of the inflammation-promoting system, rather than a simple appetite regulator. 5 Peat argued that the pharmaceutical industry initially promoted leptin as a natural anti-obesity chemical after discovering it could limit appetite, but subsequent research revealed that it is produced in excess during overeating, especially on a high-fat diet, and is particularly abundant in obese individuals. 3 He doubted the biological significance of the concept of leptin resistance, viewing it as an outgrowth of industry promotion rather than a meaningful physiological state, and suggested that being resistant to leptin might actually be beneficial given its harmful effects. 1

Mechanistically, Peat described leptin as a hormone that, when it reaches the brain, does shut off appetite but simultaneously activates inflammatory processes. 3 He specifically identified leptin as the signal that turns on the cancer metabolism known as aerobic glycolysis in breast cancer, where cancer cells inefficiently burn sugar even in the presence of oxygen. 3 Peat further elaborated that leptin, which is promoted by estrogen, activates the POMC-related endorphin stress system, and that these endorphins in turn activate histamine, another promoter of inflammation and cell division. 4 He emphasized that progesterone opposes these effects in multiple ways, including by directly inhibiting leptin. 4

Peat noted that fructose uniquely suppresses leptin relative to other foods, a point he raised in the context of defending sugar against claims that high-fructose corn syrup blocks satiety signals. 2 This aligns with his broader view that sugary fruits, which come with high concentrations of potassium and other minerals, help metabolize sugar safely without turning it into fat. 2 In contrast, Danny Roddy's early writing from 2010 presented a different framework, describing leptin as "possibly the most important hormone in the body" controlling metabolic rate and fuel regulation, and claiming that leptin resistance—caused by white sugar, grains, and vegetable oils—was the starting point of metabolic derangement and upstream of insulin resistance. 7 Roddy later acknowledged this earlier enthusiasm for leptin as a period of confusion, noting he "didn't have any idea what he's talking about" at the time. 6

Georgi Dinkov has extended the discussion by noting that despite its bad reputation, leptin is actually known to improve insulin sensitivity, with several leptin-mimetic drugs in clinical trials for treating type 2 diabetes. 8 This presents a more nuanced view of leptin's metabolic role, though it does not contradict Peat's core concern about its inflammatory and cancer-promoting actions when chronically elevated. 2 Peat's fundamental position remained that leptin is part of a regulatory system that, in obese individuals, becomes dysregulated and causes harmful effects rather than protective regulation, making it a mediator of the damage caused by obesity rather than a therapeutic target. 3