Weight, hormones and what the drugs changed

The arrival of highly effective weight medications has forced a public reconsideration of something the physiology has said for decades: body weight is regulated, not merely chosen.

The regulatory system

Fat tissue produces leptin, which signals energy stores to the hypothalamus.

The gut produces ghrelin, which stimulates appetite, and a family of satiety hormones including GLP-1, peptide YY and cholecystokinin released in response to food.

The hypothalamus integrates these signals and adjusts appetite and energy expenditure to defend a range of body weight.

Which is a system built for an environment where food was scarce, and which defends against loss far more vigorously than against gain.

What happens when weight is lost

The findings that reframed the field.

Studies following people after substantial weight loss have found persistent hormonal changes: leptin falls, ghrelin rises, satiety hormones fall, and appetite increases measurably — with these changes persisting for years rather than resolving after a period of adaptation.

Energy expenditure also falls by more than would be predicted from the smaller body size, a phenomenon described as adaptive thermogenesis.

Which means a person who has lost weight is hungrier and burns less energy than a person of the same weight who has never been heavier.

This is a physiological explanation for the well-documented pattern of weight regain, and it locates the problem somewhere other than in the individual's character.

What else influences it

Genetics, which twin and adoption studies indicate account for a substantial proportion of the variation in body weight.

Sleep, where experimental restriction alters appetite hormones and increases intake.

Medication, including several antipsychotics, some antidepressants, steroids, certain diabetes drugs and hormonal treatments.

Conditions including hypothyroidism, polycystic ovary syndrome and Cushing's syndrome.

The food environment, which has changed dramatically in the availability, energy density and marketing of highly palatable foods.

And socioeconomic factors, which correlate strongly and are frequently omitted from discussion of individual behaviour.

The GLP-1 medications

What they do and what they do not.

They mimic a gut hormone released after eating, slowing gastric emptying and acting on appetite centres in the brain.

Trial results have shown average weight losses substantially greater than any previous medication, in the range that was previously achievable only with surgery for many participants.

Cardiovascular outcome data has shown benefit in people with obesity and established cardiovascular disease, which shifted the framing from cosmetic to therapeutic.

Side effects are predominantly gastrointestinal and are the main reason for stopping; rarer serious effects exist and are why prescribing requires assessment.

Muscle mass is lost alongside fat, which is why resistance exercise and adequate protein are emphasised.

Weight is largely regained on stopping, which follows directly from the physiology above and which makes these long-term treatments rather than courses.

Supply shortages and a large market in counterfeit and compounded products have been genuine safety problems.

What this changes about the conversation

Several things.

That the failure of diets is a predictable physiological outcome rather than a moral one.

That effective treatment existing does not mean everyone should take it, since risk, cost and individual circumstance vary.

That weight stigma, which is well documented in healthcare and associated with avoidance of care and worse outcomes, is not made acceptable by the availability of treatment.

And that health improvements from physical activity, diet quality, sleep and reduced alcohol occur substantially independently of weight change, which is an important message for anyone whose weight does not change.

What still applies

The unglamorous parts remain relevant, including for people taking medication.

Protein and resistance training to preserve muscle.

Fibre and dietary quality for reasons unrelated to weight.

Sleep, which affects appetite regulation directly.

Physical activity, which has the strongest evidence of anything for maintaining weight loss and independent benefits regardless.

And attention to the environment — what is in the house, what is convenient — which acts on behaviour more reliably than intention does.

General information only, not medical advice. Consult a qualified clinician about weight and before taking any weight-loss medication — do not obtain these medications from unregulated sources.