Leptin and Melanocortin Signaling Mediates Hypertension in Offspring From Female Rabbits Fed a High-Fat Diet During Gestation and Lactation

Abstract

Maternal high-fat diet in rabbits leads to hypertension and elevated renal sympathetic nerve activity (RSNA) in adult offspring but whether this is due to adiposity or maternal programming is unclear. We gave intracerebroventricular (ICV) and ventromedial hypothalamus (VMH) administration of leptin-receptor antagonist, α-melanocyte-stimulating hormone (αMSH), melanocortin-receptor antagonist (SHU9119), or insulin-receptor (InsR) antagonist to conscious adult offspring from mothers fed a high-fat diet (mHFD), control diet (mCD), or mCD offspring fed HFD for 10d (mCD10d, to deposit equivalent fat but not during development). mHFD and mCD10d rabbits had higher mean arterial pressure (MAP, +6.4 mmHg, +12.1 mmHg, p < 0.001) and RSNA (+2.3 nu, +3.2 nu, p < 0.01) than mCD, but all had similar plasma leptin. VMH leptin-receptor antagonist reduced MAP (−8.0 ± 3.0 mmHg, p < 0.001) in mCD10d but not in mHFD or mCD group. Intracerebroventricular leptin-receptor antagonist reduced MAP only in mHFD rabbits (p < 0.05). Intracerebroventricular SHU9119 reduced MAP and RSNA in mHFD but only reduced MAP in the mCD10d group. VMH αMSH increased RSNA (+85%, p < 0.001) in mHFD rabbits but ICV αMSH increased RSNA in both mHFD and mCD10d rabbits (+45%, +51%, respectively, p < 0.001). The InsR antagonist had no effect by either route on MAP or RSNA. Hypothalamic leptin receptor and brain-derived neurotrophic factor (BDNF) mRNA were greater in mHFD compared with mCD rabbits and mCD10d rabbits. In conclusion, the higher MAP in mHFD and mCD10d offspring was likely due to greater central leptin signaling at distinct sites within the hypothalamus while enhanced melanocortin contribution was common to both groups suggesting that residual body fat was mainly responsible. However, the effects of SHU9119 and αMSH on RSNA pathways only in mHFD suggest a maternal HFD may program sympatho-excitatory capacity in these offspring and that this may involve increased leptin receptor and BDNF expression.

Protein Restriction in the Peri-Pubertal Period Induces Autonomic Dysfunction and Cardiac and Vascular Structural Changes in Adult Rats

“…This process, termed the Developmental Origins of Health and Disease, or developmental programming is not new, however the mechanisms underpinning the programming of hypertension are still being elucidated. Experimental programming models of malnutrition or nutritional imbalance during the perinatal period show that arterial hypertension may be associated with increase in vascular sympathetic tone ( Mizuno et al, 2013 ; Prior et al, 2014 ; Barros et al, 2015 ; Paulino-Silva and Costa-Silva, 2016 ; Lim et al, 2021 ) as well as redox disorganization in the brainstem ( Ferreira et al, 2016 ; Barrand et al, 2017 ; Ferreira et al, 2019 ), and heart ( Nascimento et al, 2014 ). Furthermore, the hypertension may trigger a cardiac compensatory response, leading to cardiomyocyte hypertrophy, and greater collagen deposition ( Rossini et al, 2017 ; De Jong et al, 2018 ; Assalin et al, 2019 ).…”

Maternal High-Fat Diet and Offspring Hypertension

“…The effect of a maternal HFD on the offspring has been examined in rats [ 7 , 8 ], mice [ 7 , 8 ], rabbits [ 21 ], pigs [ 22 ], and non-human primates [ 23 ]. A systematic review recruiting 17 animal studies demonstrated that maternal HFD may compromise parameters in feeding behavior and body composition of offspring [ 24 ].…”

“…Imbalanced maternal nutrition can program the fetus resulting in hypertension in later life. Table 1 summarizes animal studies documenting offspring hypertension in animal models of high-fat diet, restricting the exposure to critical periods during early development [ 21 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. In this review, we only considered studies reporting offspring outcomes starting from childhood.…”

“…Rats are the most frequently used animals. Other species such as rabbits [ 21 ] and mice [ 66 ] have also been used to study hypertension of developmental origins programmed by maternal HFD. In view of the fact that each month of the adult life of a rat corresponds to 3 human years [ 72 ], Table 1 shows the timing of developing hypertension in rats ranging from 12 weeks to 1 year of age, which corresponds to humans from childhood to adulthood.…”

“…In rodents, different maternal HFDs with fat fractions ranged from 18.7% to 58% energy as fat, which were close to previous studies [ 7 , 8 ]. Notably, maternal HFD-induced responses of offspring BP could be increased [ 21 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ] but also unaltered [ 30 , 61 ], mainly depending on sex, age, species, and varied fatty acid compositions. In Table 1 , most BP data were obtained from the tail cuff method, except some studies using direct arterial catheter [ 21 ] or telemetry method [ 61 , 62 ].…”