Effects of High-Fat Diet on Stress Response in Male and Female Wildtype and Prolactin Knockout Mice

Abstract

Prolactin (PRL) is well characterized for its roles in initiation and maintenance of lactation, and it also suppresses stress-induced responses. Feeding a high-fat diet (HFD) disrupts activity of the hypothalamic-pituitary-adrenal (HPA) axis. Whether PRL regulates HPA axis activation under HFD feeding is not clear. Male and female wildtype (WT) and PRL knockout (KO) mice were fed either a standard low-fat diet (LFD) or HFD for 12 weeks. Circulating corticosterone (CORT) levels were measured before, during, and after mice were subjected to an acute restraint stress or remained in their home cages as no stress controls. HFD feeding increased leptin levels, but the increase was lower in KO than in WT mice. All stressed female groups and only LFD-fed stressed males had elevated CORT levels compared to their no stress same-sex counterparts regardless of genotype. These results indicated that HFD consumption blunted the HPA axis response to acute stress in males but not females. Additionally, basal hypothalamic CRH content was lower in HFD than LFD males, but was similar among female groups. Furthermore, although basal CORT levels were similar among KO and WT groups, CORT levels were higher in KO mice than their WT counterparts during stress, suggesting that loss of PRL led to greater HPA axis activation. Basal PRL receptor mRNA levels in the choroid plexus were higher in HFD than LFD same-sex counterparts, suggesting activation of central PRL's action by HFD feeding in both males and females. Current results confirmed PRL's roles in suppression of the stress-induced HPA axis activation. Although HFD feeding activated central PRL's action in both sexes, only the male HPA axis was dampened by HFD feeding.

Fig 1. Body weight and caloric intake.

Body weight of male (A) and female (B) and caloric intake of male (C) and female (D) wildtype (WT) or prolactin knockout (KO) mice fed with a low-fat diet (LFD) or a high-fat diet (HFD). * Different from LFD-fed males with the same genotype at the same time points. Male: WT chow n = 28; WT HFD n = 26; KO chow n = 32; KO HFD n = 30. Female: WT chow n = 25; WT HFD n = 29; KO chow n = 28; KO HFD n = 26.

Fig 2. Body composition and plasma leptin levels.

Body fat mass of male (A) and female (B), lean mass of male (C) and female (D), and circulating leptin levels of male (E) and female (F) wildtype (WT) or prolactin knockout (KO) mice fed with a low-fat diet (LFD) or a high-fat diet (HFD). A: * Different from LFD-fed groups with the same genotype. C: * Different between LFD-fed KO males and HFD-fed KO males at the same time points. E, F: * Different from LFD-fed groups with the same sex and same genotype. † Different from levels in WT groups with the same sex and diet.

Fig 3. Plasma corticosterone levels.

Circulating corticosterone (CORT) levels of male wildtype (WT) and prolactin knockout (KO) mice fed with a low-fat diet (LFD) (A) or a high-fat diet (HFD) (B), and WT and KO males fed with a LFD (C) or a HFD (D), during 30 min restraint stress (S) or no stress control (NS). Circulating CORT levels of female WT and KO mice fed with a LFD (E) or a HFD (F), and WT and KO females fed with a LFD (G) or a HFD (H), during 30 min restraint stress (S) or no stress control (NS). A, B, E, F: * Different between genotypes with the same stress condition. † Different between stress conditions with the same genotype. C, D, G, H: § Different between diets with the same stress condition. † Different between stress conditions with the same diet. Male: WT LFD/NS n = 13; LFD/S n = 15; HFD/NS n = 13; HFD/S n = 13. KO LFD/NS n = 17; LFD/S n = 15; HFD/NS n = 14; HFD/S n = 16. Female: WT LFD/NS n = 12; LFD/S n = 13; HFD/NS n = 14; HFD/S n = 15. KO LFD/NS n = 13; LFD/S n = 15; HFD/NS n = 12; HFD/S n = 14.

Fig 4. Hypothalamic corticotrophin releasing hormone levels.

Hypothalamic corticotrophin releasing hormone (CRH) levels of male (A) and female (B) wildtype (WT) or prolactin knockout (KO) mice fed with a low-fat diet (LFD) or a high-fat diet (HFD). * Different between diets with the same genotype.

Fig 5. Prolactin receptor mRNA levels in the choroid plexus.

Prolactin receptor (PRLR) mRNA levels in the choroid plexus of male (A) and female (B) wildtype (WT) or prolactin knockout (KO) mice fed with a low-fat diet (LFD) or a high-fat diet (HFD). * Different between diets with the same genotype. † Different between genotypes with the same diet.