Beige differentiation of adipose depots in mice lacking prolactin receptor protects against high‐fat‐diet‐induced obesity

Abstract

Stimulating conversion of white fat to metabolically active adipocytes (beige fat) constitutes a promising strategy against weight gain and its deleterious associated-disorders. We provide direct evidence that prolactin (PRL), best known for its actions on the mammary gland, plays a pivotal role in energy balance through the control of adipocyte differentiation and fate. Here we show that lack of prolactin receptor (PRLR) causes resistance to high-fat-diet-induced obesity due to enhanced energy expenditure and increased metabolic rate. Mutant mice displayed reduced fat mass associated with appearance of massive brown-like adipocyte foci in perirenal and subcutaneous but not in gonadal fat depots under a high-fat diet. Positron emission tomography imaging further demonstrated the occurrence of these thermogenic brown fat depots in adult mice, providing additional support for recruitable brown-like adipocytes (beigeing) in white fat depots. Consistent with the activation of brown adipose tissue, PRLR inactivation increases expression of master genes controlling brown adipocyte fate (PRDM16) and mitochondrial function (PGC1α, UCP1). Altered pRb/Foxc2 expression suggests that this PRL-regulated pathway may contribute to beige cell commitment. Together, these results provide direct genetic evidence that PRLR affects energy balance and metabolic adaptation in rodents via effects on brown adipose tissue differentiation and function.

Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

“…There is growing evidence that the acquisition of brown-like fat cells in WAT protects against both genetic and diet-induced obesity through increased metabolic activity, and this "browning" phenomenon has become a subject of considerable interest for possible treatment of obesity and metabolic syndrome (68 -70). Browning of WAT has been shown to occur in mouse models of prolactin receptor deficiency, IkB kinase ⑀ deficiency, COXII overexpression, and increased prostaglandin synthesis (71)(72)(73)(74). In these instances, mice displayed a protection against diet-induced obesity as well as increased oxygen consumption.…”

Regulation of human subcutaneous adipocyte differentiation by EID1

“…Moreover, agonists of nuclear receptor PPARg and inhibitors of retinoblastoma protein (pRb) play important roles in the development and activation of beige cells (Auffret et al 2012, Harms & Seale 2013. The inactivation of pRb may increase levels of PGC1a (Hallenborg et al 2009, Mercader et al 2009, Lee et al 2013.…”

“…The inactivation of pRb may increase levels of PGC1a (Hallenborg et al 2009, Mercader et al 2009, Lee et al 2013. Studies in animal models show that the inactivation of pRb in adipose tissue increases mitochondrial activity levels and induces resistance to obesity (Hansen et al 2004a,b, Khidr & Chen 2006, Dali-Youcef et al 2007, Calo et al 2010, Auffret et al 2012.…”

Lactation and appetite-regulating hormones: increased maternal plasma peptide YY concentrations 3–6 months postpartum

“…Oxytocin reduces insulin resistance, increases lipolysis and exerts anti-orexigenic effects (10)(11)(12) . In contrast, prolactin increases the central resistance to leptin, stimulates appetite and promotes high-fat diet-induced obesity (13,14) .…”

“…Oxytocin reduces insulin resistance, increases lipolysis and exerts anti-orexigenic effects (10)(11)(12) . In contrast, prolactin increases the central resistance to leptin, stimulates appetite and promotes high-fat diet-induced obesity (13,14) .Appetite-regulating hormones derived from the gut may also be affected by the complex neuroendocrine changes accompanying lactation, as they are subject to tight regulatory feedbacks within the gut-brain axis and are closely related to alterations of energy metabolism (15,16) . Indeed, the gastrointestinal expression and circulating concentrations of the anorexigenic hormone peptide YY (PYY) were increased throughout the lactation period in rodents, whereas ghrelin levels remained unchanged (17) .…”