Leptin resistance during pregnancy is also exerted at the periphery†

Abstract

Pregnancy is a physiological state with a great demand of energy and nutrients in mammals and is characterized by hyperphagia, increase in fat mass, hyperleptinemia, and central resistance to leptin. In order to evaluate whether pregnancy is also a state of leptin resistance at the periphery, we studied the response to leptin in the liver and subcutaneous adipose tissue (SAT). We demonstrated reduced levels of phosphoryalated signal transducer and activator of transcription 3 (p-STAT3) and phosphorylated protein kinase B (p-AKT) after intravenous leptin in both tissues in mid-term pregnant rats (G13) and a restored response in late pregnancy (G18). As underlying mechanisms of the peripheral leptin resistance of mid-gestation we found decreased leptin receptor b (LepRb) mRNA levels and increased content of suppressor of cytokine signaling 3 (SOCS3). Furthermore, we demonstrated that in G13 rats the main lipogenic molecules and activity (sterol regulatory element binding transcription protein 1 (SREBP-1) and fatty acid synthase (FAS)) were elevated in the liver and SAT, and the molecules involved in β-oxidation (peroxisome proliferator activated receptor α (PPARα) and carnitine palmitoyltransferase 1 (CPT-1)) were reduced, as it happens in early pregnancy. In G18, the opposite pattern is observed. This probably reflects that in G13 the peripheral resistance to the hyperleptinemia might help maintaining the lipogenic metabolism of early pregnancy. In contrast, the recovery of the response to leptin in late pregnancy would favor a catabolic metabolism. Finally, using a pseudogestation model we showed that progesterone and prolactin are not involved in the gestational peripheral leptin resistance. In conclusion, during mid-pregnancy a state of leptin resistance is also exerted at the periphery, and is probably involved in the characteristic lipid regulation of this physiological state.

Maternal nutrient metabolism in the liver during pregnancy

“…Maternal obesity during pregnancy increases the risk of offspring developing obesity, and obesity is characterized by elevated levels of leptin in pregnant females ( 112 ). A state of leptin resistance in the liver during mid-pregnancy helps maintaining lipogenic metabolism, but an opposite pattern in late pregnancy favors catabolic metabolism in the liver, which is independent of progesterone and prolactin ( 113 ). Therefore, the mechanism by which leptin regulates maternal hepatic lipid metabolism requires investigation in the future.…”

Does Altered Cellular Metabolism Underpin the Normal Changes to the Maternal Immune System during Pregnancy?

“…Usually produced in adipose tissue, placenta-derived leptin emerges as a novel pregnancy hormone and during the second and third trimester plasma leptin levels become elevated including a contribution of the placenta as a pregnancy-specific source of leptin [ 77 , 78 ]. Leptin resistance develops during the second trimester and has a role in supporting the growth of the fetus [ 79 , 80 ], whilst maternal obesity has been associated with further leptin resistance in the placenta [ 81 ]. While the leptin-rich environment that presents during the second and third trimester might be expected to contradict the known effects of leptin on Treg number, the accompanying leptin resistance would favour increased Tregs [ 73 , 74 ], although we do not know if this leptin resistance extends to the immune system and more specifically Treg cells.…”

The Role of Hyperleptinemia in the Genesis of Gestational Hypertension and Preeclampsia

“…Також доведено, що в генезі надмірної гестаційної гіперлептинемії лежить лептинорезистентність внаслідок синцитіотрофо бласт зниженої регуляції лептинових рецепторів на фоні підвищеного рівня лептину в крові. Розвиток лептинорезистентності у цих пацієнток веде до зниження засвоєння глюкози тканинами, окислення жирів, сигналізує про необхідність підвищити споживання їжі, що веде до патологічного збільшення маси тіла [4].…”