Lipocalin 2 as a Regulator of Phospholipid Metabolism in Adipose Mitochondrial Bioenergetics

Healthy adipose tissue function is essential for maintaining metabolic homeostasis and preventing metabolic diseases. While hypertrophic expansion of adipocytes can lead to adipose tissue dysfunction and contribute to obesity-related metabolic complications, expansion through hyperplasia, driven by adipogenesis, can serve as a protective mechanism. Impaired adipogensis is associated with obesity and aging, promoting the development of metabolic syndrome. Therefore, understanding the mechanisms behind impaired adipogenesis is crucial for designing therapeutic strategies to combat metabolic diseases.

In both human and mouse obesity, defective adipogenesis has been linked to senescence in adipose progenitor cells. Recent evidence suggests that extracellular vehicles (EVs) play a role in intercellular communication within adipose tissue and regulate adipose tissue function. However, the specific EVs responsible for regulating adipoegnesis and the factors controlling the secretion and adipogenic function of EVs remains unexplored. Our preliminary studies indicate that Lipocalin 2 (Lcn2), as a novel phosphatidic acid (PA) binding protein, plays a regulatory role in senescence and adipogenesis of adipocyte progenitors through EV-mediated intercellular communication.

Lcn2 deficiency impairs adipogenesis and results in hypertrophic obesity under high fat diet conditions. Stromal-vascular (SV) cells from brown and white adipose tissue of Lcn2 knockout (KO) mice exhibit increased senescence and decreased adipogenesis. Additionally, we have discovered that Lcn2 is present in a specific population of small EVs secreted by adipocytes. Lcn2 deficiency reduces the small EV population and the secretion of EVs from adipocytes, particularly under inflammatory conditions.

Our recent investigations unveiled a pivotal role of Lcn2 as a PA binding protein in the recursive regulation of phospholipase 2 (PLD2)-PA loop and PA production, which is crucial for EV biosynthesis and secretion. Our hypothesis is that Lcn2 functions as an anti-senescence factor that maintains the health of adipose stem and progenitor cells (ASPCs) via regulating EV-mediated intercellular communication within adipose tissue. This one-year project proposes two Aims. Aim1 will establish the protective role of Lcn2 against senescence and adipogenic defects in ASPCs during diet-induced obesity, focusing on anti-senescence and adipogenic effects of Lcn2 overexpression in adipocytes.

Aim2 will determine the role of Lcn2 in EV-mediated intercellular communication necessary for maintaining the adipogenic function of ASPCs. We will characterize the role of Lcn2 in the release and cargo loading of EVs from adipocytes in response to metabolic stress and inflammatory stimulation. The findings from this project will provide new insights into the pathogenesis of hypertrophic obesity and to pave the way for the development of novel therapeutic approaches.

Grant Number: 2R56DK123042-05A1
NIH Institute/Center: NIH
Principal Investigator: XIAOLI CHEN