Dataset Information

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.

ABSTRACT: Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phenotyping in this rat model as well as in transgenic mice reveals that the effects of prolonged suckling are mediated by increased hepatic fibroblast growth factor 21 (FGF21) production and tanycyte-controlled access to the hypothalamus in adulthood. Specifically, FGF21 activates GABA-containing neurons expressing dopamine receptor 2 in the lateral hypothalamic area and zona incerta. Prolonged breastfeeding thus constitutes a protective mechanism against obesity by affecting long-lasting physiological changes in liver-to-hypothalamus communication and hypothalamic metabolic regulation.

SUBMITTER: Pena-Leon V

PROVIDER: S-EPMC9314260 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.

Pena-Leon Veronica V Folgueira Cintia C Barja-Fernández Silvia S Pérez-Lois Raquel R Da Silva Lima Natália N Martin Marion M Heras Violeta V Martinez-Martinez Sara S Valero Paola P Iglesias Cristina C Duquenne Mannon M Al-Massadi Omar O Beiroa Daniel D Souto Yara Y Fidalgo Miguel M Sowmyalakshmi Rasika R Guallar Diana D Cunarro Juan J Castelao Cecilia C Senra Ana A González-Saenz Patricia P Vázquez-Cobela Rocío R Leis Rosaura R Sabio Guadalupe G Mueller-Fielitz Helge H Schwaninger Markus M López Miguel M Tovar Sulay S Casanueva Felipe F FF Valjent Emmanuel E Diéguez Carlos C Prevot Vincent V Nogueiras Rubén R Seoane Luisa M LM

Nature metabolism 20220725 7

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood and throughout adulthood remain largely unknown. Here we show that delayed weaning in rat pups protects them against diet-induced obesity in adulthood, through enhanced brown adipose tissue thermogenesis and energy expenditure. In-depth metabolic phe ...[more]

PMID: 35879461

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Project description:Increased glucocorticoid (GC) levels act as a master contributor to central obesity in estrogen-depleted females; however, what factors cause their increased GC production is unclear. Given (1) liver fibroblast growth factor 21 (FGF21) and GCs regulate each other's production in a feed-forward loop, and (2) circulating FGF21 and GCs are parallelly increased in menopausal women and ovariectomized mice, we thus hypothesized that elevation of hepatic FGF21 secretion causes increased GGs production in estrogen-depleted females. Using the ovariectomized mice as a model for menopausal women, we found that ovariectomy (OVX) increased circulating corticosterone levels, which in turn increased visceral adipose Hsd11b1 expression, thus causing visceral obesity in females. In contrast, liver-specific FGF21 knockout (FGF21 LKO) completely reversed OVX-induced high GCs and high visceral adipose Hsd11b1 expression, thus abrogating OVX-induced obesity in females. Even though FGF21 LKO failed to rescue OVX-induced dyslipidemia, hepatic steatosis, and insulin resistance. What's worse, FGF21 LKO even further exacerbated whole-body glucose metabolic dysfunction as evidenced by more impaired glucose and pyruvate tolerance and worsened insulin resistance. Mechanically, we found that FGF21 LKO reduced circulating insulin levels, thus causing the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes in OVX mice. Collectively, our results suggest that liver FGF21 plays an essential role in mediating OVX-induced central obesity by promoting GC production. However, lack of liver FGF21 signaling reduces insulin production and in turn causes the dissociation between decreased central obesity and the improvement of obesity-related metabolic syndromes, highlighting a detrimental role for hepatic FGF21 signals in mediating the development of central obesity but a beneficial role in preventing metabolic abnormality from further exacerbation in estrogen-depleted females.

Dataset Information

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.

Publications

Prolonged breastfeeding protects from obesity by hypothalamic action of hepatic FGF21.

Similar Datasets

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