Beige differentiation of adipose depots in mice lacking prolactin receptor protects against high-fat-diet-induced obesity.
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.
Institut National de Santé et de Recherche Médicale (INSERM) U693, Le Kremlin-Bicêtre, France.
Julien
J
Auffret
Say
S
Viengchareun
Nadège
N
Carré
Raphaël G P
RG
Denis
Christophe
C
Magnan
Pierre-Yves
PY
Marie
Adeline
A
Muscat
Bruno
B
Fève
Marc
M
Lombès
Nadine
N
Binart
D002001:Adipose Tissue, Brown / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D017931:DNA Primers; D004041:Dietary Fats / Q000008:administration & dosage*; D015870:Gene Expression; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D049268:Positron-Emission Tomography; D060888:Real-Time Polymerase Chain Reaction; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis
D017931:DNA Primers; D004041:Dietary Fats; D011981:Receptors, Prolactin