Research
Hormonal
The human energy homeostatic system is evolutionarily biased towards weight gain and fat storage, making long-term weight loss difficult to achieve through diet and exercise alone.
Understand that your body is designed to regain lost weight. This is not a moral failing but a biological reality driven by hormones like leptin and neuropeptide Y. Long-term success often requires addressing these hormonal drivers, potentially through medical interventions, rather than relying solely on willpower.
GoodSupportsHIGH confidence
There has been little evolutionary pressure to reduce intake to low levels once energy stores are replete, or to burn off excess calories as heat. Hence this homeostatic system is biased strongly towards weight gain and storage of fat, with few mechanisms that encourage weight loss.
Why this rating
Supported by extensive animal models and human clinical observations of leptin resistance.
Source
Neuropeptides and appetite control
John Wilding · Diabetic Medicine · 2002
DOI 10.1046/j.1464-5491.2002.00790.x
narrative_reviewCited 188×
Read the paper DOI resolved against Crossref · corpus check 2026-06-10
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- Leptin resistance in common obesity prevents the hormone from signaling satiety to the brain, rendering high circulating levels ineffective for weight loss.Good
- Neuropeptide Y (NPY) and Agouti-Related Protein (AGRP) are potent orexigenic peptides that increase food intake and decrease energy expenditure, particularly when leptin signaling is low.Good
- Alpha-melanocyte-stimulating hormone (α-MSH) and Cocaine- and Amphetamine-Regulated Transcript (CART) reduce food intake and increase energy expenditure, acting as counter-regulatory peptides to NPY and AGRP.Good
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