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

♀

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.