The 75-Year-Old Obesity Riddle Science Just Solved
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Hidden inside this letter is a secret: a scientific breakthrough 75 years in waiting. Fat cells send secret letters to the brain; the information coded within them controls hunger, metabolism, and answers a near century-old riddle that could reverse obesity. If biology writes the right messages, we feel satiated, energetic, stay lean and healthy. If it writes the wrong messages to the brain, we become hungry, sluggish, end up sick and fat.
For 75 years, we've had no idea what's actually inside the letter, what's the message. A brand new study opens the letter, revealing something consequential and fascinating.
Biology thwarted us. Why these messages can be rewritten is the trillion-dollar question. This is a genuine breakthrough in understanding obesity.
More nuances, details, references, and written breakdown at the newsletter at staycuriousmetabolism.com.
In 1949, researchers at Jackson Laboratory accidentally discovered mutant mice deficient in leptin, causing them to balloon up as fat cells forgot how to say stop, developing severe obesity. Humans with congenital leptin deficiency also develop severe obesity.
Leptin signals the brain to reduce appetite and increase energy expenditure. Loss of leptin causes severe obesity. Giving leptin back to these obese mice or patients reverses obesity. Scientists thought they discovered the cause and cure of obesity.
Giving leptin to normal fat mice or humans with diet-induced obesity doesn't have the same anti-obesogenic effect because the body and brain become leptin resistant. Leptin levels go up in obesity, but the brain stops listening, resulting in increased hunger, decreased energy expenditure, and metabolic dysfunctions.
Analogy: Leptin resistance is like fullness and satiety centers of the brain turning on do not disturb.
For decades, scientists puzzled over what causes leptin resistance in the brain. A new study published in Cell Metabolism identifies the specific letters fat cells mail to the brain and the molecular code determining how the brain responds to leptin.
In obesity, these molecular letters become metabolically abusive, writing the code for leptin resistance. Discovering their contents allows rewriting the message.
Researchers used RAB27 knockout mice with a defect in fat cells preventing them from mailing out letters (extracellular vesicles). These are little membrane-bound packages carrying cargo to the brain.
When fat cells couldn't send these extracellular vesicles, mice gained fat mass (not lean mass), with increased food intake, decreased oxygen consumption, and decreased body temperature: hungrier, ate more, metabolism slowed, leading to obesity and metabolic dysfunction.
Healthy mice extracellular vesicles injected into obese mice unable to make their own caused rapid fat loss. But extracellular vesicles from diet-obese mice didn't work.
Diet rewrites the message in the letters. Fat cells in diet-induced obesity still make letters, but messages change, perpetuating obesity.
Extracellular vesicles from lean humans given to mice unable to make their own caused fat loss. From obese humans, the effect disappeared. This pathway is highly conserved across species; transferable between species, relevant to humans.
Mice with fluorescent-tagged (mCherry) extracellular vesicles showed brains lit up like Times Square: clear direct evidence letters reach the brain.
Summary: In lean state, healthy small fat cells send extracellular vesicle letters with instructions maintaining leanness, fullness, energy expenditure. In obesity, letters corrupted, message changes, leading to increased hunger, decreased energy expenditure.
The message: small non-coding strings of nucleotides, microRNA (like modified RNA strips). They don't produce proteins but modify gene expression and signaling pathways.
Chopping up microRNAs from healthy letters eliminated anti-obesity effects. In diet-induced obesity, microRNAs causing leptin resistance increase; those promoting leptin sensitivity decrease. Opposite in healthy lean state.
Pattern holds in mice and humans, including study of over 100 individuals across BMI spectrum. In overweight/obesity (BMI >25), leptin-sensitizing microRNAs depleted, causing leptin resistance. Dose-dependent: higher BMI associates with lower levels of healthy microRNAs.
Example: MIR148A-3p enhances leptin sensitivity, suppresses obesity.
In human obesity patients treated with bariatric surgery (inducing weight loss), leptin-sensitizing microRNAs rise, promoting sensitivity, fighting resistance.
These messages can be rewritten.
Synthesizing these microRNAs, packaging into extracellular vesicles, administered to animals reversed obesity in preclinical experiments.
Decades ago, leptin seemed to solve obesity, but leptin resistance blocked it. For 75 years, efforts failed to crack the code. This identifies part of the answer: in diet-induced obesity, extracellular vesicle letters rewritten in microRNA code drive leptin resistance. Intercepting/replacing messages enhances sensitivity, potentially reverses obesity, addressing core metabolic dysfunction.
Distinct from GLP-1 drugs (e.g., semaglutide) that super-physiologically dose hormones. This targets root cause of hormonal resistance like insulin resistance or leptin resistance: genuine breakthrough, consequential, fascinating. Glimpse of the future.
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