Obesity: Biological Drivers and Evidence-Based Therapeutic Approaches

Obesity is not a matter of weak willpower — it is a biologically driven metabolic disorder shaped by disrupted appetite signals, hormonal imbalance, and an environment our bodies were never designed for.

The old idea of “eat less, move more” collapses when we look at the science. Human physiology is built for survival, not for modern calorie-dense living, and the systems meant to regulate hunger and metabolism easily become overwhelmed.

When excess nutrition and inactivity persist, central appetite circuits begin to malfunction. Leptin — the hormone that should tell the brain “you’ve had enough” — struggles to cross the blood–brain barrier, with its transport efficiency dropping by nearly 80% in obesity. As a result, the brain doesn’t receive strong satiety signals, even when the body has more than enough energy stored.

Insulin, another key regulator of satiety and nutrient use, also loses its effectiveness. Chronic overeating, poor sleep, and inactivity drive insulin resistance, causing free fatty acids to overflow into organs not designed to store them — a toxic process known as lipotoxicity. Ghrelin pathways shift too, with blunted receptor sensitivity contributing to persistent hunger and cravings.

Deep within the hypothalamus, the balance between POMC pathways (which reduce appetite) and NPY/AgRP pathways (which stimulate it) becomes distorted. Over time, these circuits grow desensitized, amplifying hunger and weakening metabolic control. Layered on top of this are inflammation, mitochondrial stress, disrupted circadian rhythms, and changes in gut microbiota — each reinforcing the next and locking the body into metabolic dysfunction.

Obesity emerges not from personal failure, but from a survival system pushed beyond its limits by today’s environment.

Clinical conversations must shift accordingly: real care means focusing on metabolic pathways, sleep, stress, circadian health, and central appetite biology — not blame. Treat the biology, support the person, and address obesity for what it truly is: a chronic metabolic disease, not a character flaw.

(Source: Kong Y, Yang H, Nie R, Zhang X, Zuo F, Zhang H, Nian X. Obesity: pathophysiology and therapeutic interventions. Mol Biomed. 2025;6(1):1-41.)