Leptin Function and Regulation
Leptin is an appetite-suppressing hormone produced by adipose tissue in proportion to total body fat mass. It signals to the hypothalamus (a brain region controlling hunger, satiety, and energy expenditure) that adequate energy stores exist. High leptin levels suppress appetite and increase energy expenditure; low leptin levels increase appetite and reduce expenditure.
Leptin During Caloric Restriction
Acute Leptin Decline
During caloric restriction, leptin levels drop sharply and rapidly—often within days to weeks of starting a deficit. This drop occurs independently of fat loss (it reflects current caloric deficit rather than accumulated fat loss). The acute leptin decline triggers compensatory increases in hunger hormones including ghrelin and neuropeptide Y.
Hypothalamic Adaptation
The hypothalamus senses low leptin as a signal of energy scarcity. This triggers a cascade of adaptive responses:
- Increased appetite drive and food-seeking behaviour
- Suppression of satiety signalling
- Reduction in energy expenditure signals
- Alterations in reproductive and immune function (lower-priority metabolic processes)
Refeeding and Leptin Recovery
During refeeding, leptin levels rise again as energy intake increases and fat mass is restored. However, leptin recovery is often slower and less complete than the initial drop. Additionally, the magnitude of leptin increase may be blunted relative to the degree of weight regain, suggesting altered leptin secretion or metabolism.
Leptin Resistance Development
Mechanism of Resistance
Repeated weight cycling, particularly when followed by preferential fat regain, can result in leptin resistance. This is a condition in which the hypothalamus becomes less sensitive to leptin signals despite normal or elevated leptin levels. The mechanisms include:
- Reduced expression of leptin receptors in the hypothalamus
- Impaired intracellular signalling downstream of leptin receptors
- Increased inflammatory signalling that interferes with leptin signalling
- Altered trafficking of leptin receptors
Functional Consequences
When the hypothalamus becomes resistant to leptin, it fails to appropriately suppress appetite or increase energy expenditure despite adequate or elevated leptin levels. This creates a paradoxical situation: the body "thinks" it is in energy deficit and needs to eat more, even though fat stores are abundant. This contributes to sustained elevated hunger in individuals with a history of repeated dieting.
Other Appetite Hormones
Ghrelin Changes
Ghrelin, an appetite-stimulating hormone, increases during restriction and often remains elevated during early refeeding. The delayed normalisation of ghrelin contributes to continued elevated hunger signals even after energy intake has increased.
Peptide YY and GLP-1
These satiety-promoting peptides show altered secretion in weight-cycling individuals, with blunted postprandial (after-eating) responses. This reduces the satiety signalling that normally constrains food intake after meals, contributing to difficulty with appetite control.
Cumulative and Persistent Effects
Leptin resistance and related appetite hormone disturbances appear to be cumulative—increasing in magnitude and persistence with repeated cycles. An individual with a single weight-loss episode may show temporary leptin resistance that resolves within months of achieving weight stability. However, individuals with multiple cycling episodes may show chronic, persistent leptin resistance that does not fully resolve.
Neuroadaptation and Learned Responses
Beyond hormonal changes, the hypothalamus undergoes neuroadaptation through repeated experiences of restriction and refeeding. Learned associations between environmental cues and food availability, combined with dopaminergic reward signalling, can create conditioned responses that persist even after hormonal adaptations partially resolve. This neurobiological learning contributes to the psychological difficulty of weight management after repeated dieting.
Individual Variation
The degree to which leptin resistance develops varies between individuals. Genetic factors, baseline insulin sensitivity, inflammatory status, and sleep quality all influence individual susceptibility to leptin resistance from weight cycling. Some individuals may show minimal changes despite repeated cycles, whilst others develop substantial resistance.