Leptin in the VMH contributes to the initial overconsumption of palatable diets by rats

Deleting leptin receptors from VMH steroidogenic factor 1-expressing neurons exaggerates diet-induced obesity in mice. Experiments described here tested whether VMH leptin receptors prevent obesity in rats. Male, but not female, Sprague-Dawley rats increased energy intake for 3 days when offered a 45% kcal fat high-fat (HF) diet. There was no change in body composition of either sex during 60 days of HF feeding. Basal leptin signaling was not changed during overeating, but hindbrain leptin activity was downregulated when HF-fed rats corrected energy intake. Male and female rats exhibited increased sensitivity to VMH leptin only during the early days of being offered an HF diet. Deletion of VMH leptin receptor-expressing cells using leptin-saporin (Lep-Sap) prevented the initial hyperphagia in males but did not change subsequent energy intake, expenditure, adiposity, or glucose clearance compared with rats fed a 10% kcal fat diet. Surprisingly, HF-fed Lep-Sap rats responded to peripheral injection of leptin, whereas LF-fed Lep-Sap rats did not. Male Lep-Sap rats showed increased preference for a 2% sucrose solution but were more accurate than control blank-Sap rats in compensating for consumption of a 10% sucrose solution. Similarly, Lep-Sap rats offered a choice diet of lard, 30% sucrose, and chow increased energy intake and body fat mass but consumed less than blank-Sap rats during the first 4 days on the diet by decreasing chow intake. These results suggest that VMH leptin receptors in rats contribute to the early overconsumption of palatable diets and that this is reversed when leptin signaling in the nucleus tractus solitarius and VMH is downregulated.NEW & NOTEWORTHY When rats are offered a high-fat diet, they overeat for the first few days, and then energy intake decreases to a lower, stable level. Experiments described here demonstrate that leptin receptors in the ventromedial hypothalamus of rats are required for this overeating. Loss of these receptors appears to result in an increased preference for sucrose solution but a greater precision of the control of energy intake.