Leptin

Leptin is a peptide hormone secreted primarily by white adipose tissue. Circulating leptin levels are roughly proportional to total body fat mass, making leptin the principal signal by which the hypothalamus tracks long-term energy stores.

Physiological role

• Appetite suppression — acts on POMC/CART neurons in the arcuate nucleus, opposing ghrelin's appetite-stimulating effect.
• Energy expenditure — falling leptin reduces BMR, suppresses NEAT, and slows thermogenesis.
• Thyroid axis — low leptin suppresses TSH and T3 conversion.
• Reproductive function — below-threshold leptin halts menstruation in women; the hypothalamus reads it as a famine signal.

Leptin in caloric deficit

This is where leptin becomes critical for tracking and body-composition contexts. When caloric intake drops below maintenance, leptin falls. The fall starts within days — before meaningful fat loss — because leptin responds to acute energy flux, not just stored fat. Sustained deficit drives leptin well below what would be predicted by fat-mass alone.

The consequences of low leptin are the set of signals that make extended dieting hard: increased hunger, decreased satiety, reduced spontaneous movement (NEAT), slowed BMR, elevated thyroid-pathway suppression. This cluster is the physiological core of adaptive thermogenesis.

Leptin resistance

Most individuals with obesity have markedly elevated fasting leptin — often 10–20× the level of a lean person — yet do not experience the expected satiety effect. This is leptin resistance: the hypothalamus has become less responsive to leptin's satiety signal, in a pattern analogous to the insulin resistance of type 2 diabetes. The mechanism is incompletely understood; candidates include inflammation-mediated signalling interference, SOCS3 induction in hypothalamic neurons, and impaired blood-brain barrier transport of leptin.

Why "just eat less" is biologically costly

After meaningful weight loss, leptin remains suppressed for months — often a year or more — even when fat mass has stabilised. This is the biological context for the persistent hunger observed by Sumithran et al. (2011) in post-weight-loss subjects. A person who has dropped 20% of body fat mass is operating on a hypothalamus receiving a persistent "famine" signal.

Practical implications for tracking

• Refeeds and diet breaks modestly raise leptin, which is one theoretical basis for their inclusion in longer cuts.
• Very-low-calorie dieting drops leptin fastest and hardest — one reason it carries worse long-term outcomes than moderate-deficit approaches.
• Sleep deprivation independently suppresses leptin, compounding dieting hunger.

Leptin therapy

Exogenous leptin has limited utility in common obesity — because the problem is resistance, not deficiency — but is profoundly effective in the rare cases of congenital leptin deficiency. Leptin is also used in research contexts to study the adaptive-thermogenesis response to weight loss.