Characterization of the resistance to the anorectic and endocrine effects of leptin in obesity-prone and obesity-resistant rats fed a high fat diet

Leptin produced by adipocytes controls body weight by
restraining food intake and enhancing energy expenditure
at the hypothalamic level. The diet-induced increase in fat
mass is associated with the presence of elevated circulating
leptin levels, suggesting the development of resistance to
its anorectic effect. Rats, like humans, show different
susceptibility to diet-induced obesity. The aim of the
present study was to compare the degree of leptin resistance
in obesity-prone (OP) vs obesity-resistant (OR) rats
on a moderate high-fat (HF) diet and to establish if the
effects of leptin on hypothalamo–pituitary endocrine functions
were preserved. Starting from 6 weeks after birth,
male Sprague–Dawley rats were fed on either a commercial
HF diet (fat content: 20% of total calorie intake) or a
standard pellet chow (CONT diet, fat content: 3%). After
12 weeks of diet, rats fed on HF diet were significantly
heavier than rats fed on CONT diet. Animals fed on HF
diet were ranked according to body weight; the two tails
of the distribution were called OP and OR rats respectively.
A polyethylene cannula was implanted into the
right ventricle of rats 1 week before central leptin administration.
After 12 weeks of HF feeding, both OR and OP
rats were resistant to central leptin administration (10 μg,
i.c.v.) (24 h calorie intake as a percent of vehicle-treated
rats: CONT rats, 62 [50; 78]; OR, 93 [66; 118]; OP, 90
[70; 120] as medians and 95% confidence intervals (CIs) of
six rats for each group). Conversely, after 32 weeks of diet
both OR and OP rats were partially responsive to 10 μg
leptin i.c.v. as compared with CONT rats (24 h calorie
intake as a percent of vehicle-treated rats: CONT rats, 60
[50; 67]; OR, 65 [50; 80]; OP, 80 [60; 98] as medians and
95% CIs of six rats for each group); the decrease of food
intake following 200 μg leptin i.p. administration was
similar in all the three groups (calorie intake as a percent of
vehicle-treated rats: 86 [80; 92] as median and 95% CI).
The long-term intake of HF diet caused hyperleptinemia,
hyperinsulinemia and higher plasma glucose levels in OP
rats as compared with CONT rats. Plasma thyroxine (T4)
was lower in all the rats fed the HF diet as compared with
CONT. i.c.v. administration of leptin after 32 weeks of
diet restored normal insulin levels in OP rats. Moreover,
leptin increased plasma T4 concentration and strongly
enhanced GH mRNA expression in the pituitary of OP as
well as OR rats (18010% vs vehicle-treated rats). In
conclusion, long-term intake of HF diet induced a partial
central resistance to the anorectic effect of leptin in both
lean and fat animals; the neuroendocrine effects of leptin
on T4 and GH were preserved.