Table 4.

Unified model for how the competing hepatic thriftiness and non-hepatic set point programmes interact to produce the observed phenotypes in males and females

	Cohort	Metabolism1	Set point calibration2	Set point enforcement3	Phenotypic consequences
♀	AD/Sal	Normal	Normal	Strong (female default)	Baseline for chow and high fat diet regimes in females.
	AD/Lep	Thrifty	Normal	Strong (female default)	Normal set point calibration is enforced and overrides the thrifty metabolism. Weight remains comparable to AD/Sal females on both low and high fat diets despite thrifty liver biochemistry.
	UN/Sal	Thrifty	Lean	Impaired (due to insufficient leptin availability)	Set point enforcement is impaired and consequently unable to compensate for a thrifty metabolism when fed a HF diet. UN/Sal/HF females become morbidly obese and suffer metabolic syndrome.
	UN/Lep	Thrifty	Lean	Strong (restored to female default level)	A well-enforced “lean” set point in rescued females compensates for the thrifty metabolism, enforcing a lean body composition in UN/Lep/Chow and keeping weight gain down to normal levels in UN/Lep/HF.
♂	AD/Sal	Normal	Normal	Weak (male default)	Baseline for chow and high fat diet regimes in males.
	AD/Lep	Thrifty	Normal	Weak (male default)	As with UN/Sal animals (male and female), set point enforcement is weak and cannot compensate for the thrifty metabolism. The AD/Lep HF phenotype is more severe than UN/Sal/HF because the set point is higher.
	UN/Sal	Thrifty	Lean	Severely impaired (weak male default is lowered further)	Set point enforcement is severely impaired and thus UN/Sal males cannot maintain a steady body composition even on a normal chow diet. However, the set point is still lean and so the phenotype on HF diet is less severe than AD/Lep males.
	UN/Lep	Thrifty	Lean	Weak (restored to male default level)	Combined programme is similar to UN/Sal females. Rescued males maintain a steady body composition on a normal chow diet but show elevated weight gain on HF diet.

¹The thrifty metabolic programme is induced by periods of restricted growth, whether due to maternal undernutrition or postnatal leptin treatment, and is consequently present in all except AD/Sal cohorts.

²The level of the set point is established by the body composition at the time of the neonatal leptin surge, and is consequently normal for AD cohorts and lean for UN cohorts.

³The strength with which the set point calibration is enforced depends on the levels of leptin at the time of calibration. Set point enforcement is weaker in males than in females for unknown reasons.