The postnatal leptin surge in mice is variable in both time and intensity and reflects nutritional status

Abstract

Background/objectives The murine postnatal leptin surge occurs within the first 4 weeks of life and is critical for neuronal projection development within hypothalamic feeding circuits. Here we describe the influence of nutritional status on the timing and magnitude of the postnatal leptin surge in mice. Methods Plasma leptin concentrations were measured 1–3 times per week for the first 4 weeks of life in C57BL/6J pups reared in litters adjusted to 3 (small), 7–8 (normal), or 11–12 (large) pups per dam fed breeder chow or raised in litters of 7–8 by dams fed high-fat diet (HFD) ad libitum starting either prior to conception or at parturition. Results Mice raised in small litters become fatter than pups raised in either normal or large litters. The leptin surge in small litter pups starts earlier, lasts longer, and is dramatically larger in magnitude compared to normal litter pups, even when leptin concentrations are normalized to fat mass. In mice reared in large litters, weight gain is diminished and the surge is both significantly delayed and lower in magnitude compared to control pups. Pups reared by HFD-fed dams (starting preconception or at parturition) are fatter and have augmented leptin surge magnitude compared to pups suckled by chow-fed dams. Surge timing varies depending upon nutritional status of the pup; the source of the surge is primarily subcutaneous adipose tissue. At peak leptin surge, within each group, fat mass and plasma leptin are uncorrelated; in comparison with adults, pups overproduce leptin relative to fat mass. Plasma leptin elevation persists longer than previously described; at postnatal day 27 mice continue overproducing leptin relative to fat mass. Conclusions In mice, small litter size and maternal HFD feeding during the perinatal period augment the plasma leptin surge whereas large litter size is associated with a delayed surge of reduced magnitude.

The Role of Leptin in the Development of Energy Homeostatic Systems and the Maintenance of Body Weight

“…There is strong evidence that maternal HFD feeding during perinatal period as well as overnutrition of sucking pups (by decreasing litter size) increases body weight and predisposes the offspring to greater weight gain when exposed to HFD in adulthood (Ainge et al, 2011;Lagisz et al, 2015;Ribaroff et al, 2017). Some of the leptin-related consequences of overfeeding in rodents are related to the magnitude of the postnatal leptin surge (Marangon et al, 2020;Skowronski et al, 2021), leptin sensitivity in the CNS (Kirk et al, 2009), neuroanatomy of the leptin-dependent feeding circuits (Kirk et al, 2009;Vogt et al, 2014), and epigenetic changes-specifically hypermethylation of the hypothalamic POMC promoter (Plagemann et al, 2009;Marco et al, 2014).…”

“…In rats and mice (Marangon et al, 2020;Skowronski et al, 2021), maternal high fat diet (HFD) feeding during gestation and/or lactation, or overfeeding the pups via reduced litter size augments the postnatal leptin surge (see below) and subsequent weight in the offspring. Caloric or protein restriction of dams or underfeeding the pups by increased litter size reduces and delays the leptin surge with a reduction in weight into adulthood (Delahaye et al, 2008).…”

“…Caloric or protein restriction of dams or underfeeding the pups by increased litter size reduces and delays the leptin surge with a reduction in weight into adulthood (Delahaye et al, 2008). Skowronski et al (2021) demonstrated that all pups undergo a postnatal leptin surge, but in the underfed state, the surge is delayed and transitory. Excess or deficiency in leptin does not affect body weight and adiposity of pups prior to the second week of life.…”

Reverting to a Healthy Diet during Lactation Normalizes Maternal Milk Lipid Content of Diet‐Induced Obese Rats and Prevents Early Alterations in the Plasma Lipidome of the Offspring

“…[ 5 ] Noteworthy, both maternal obesity and the intake of an obesogenic diet during lactation have been related to a detrimental and persistent impact on the development of the neonates. [ 6–8 ] Although the specific mechanisms involved are only partially understood, [ 9 ] milk quality may represent one of the key factors. [ 10 ] Thus, intervention studies in rodents have shown that the intake of an obesogenic diet during the perinatal period negatively affects the structure and function of the mammary gland and therefore the composition of milk, [ 11 ] including altered metabolism‐regulating hormones and fatty acids (FA) profiles.…”

In vivo neuroimaging evidence of hypothalamic alteration in Prader–Willi syndrome

“… 40 The resultant exposure of the PWS foetus to a restricted nutritional environment we suggest may impact on subsequent leptin-induced foetal hypothalamic development pre- and post-natally, which has been shown to be dependent on nutritional status. 41 , 42 These hypotheses require further study in animal models of PWS and where possible longitudinally in humans, and here we present preliminary evidence in young adults of hypothalamic dysfunction.…”