Functional Differences in Visceral and Subcutaneous Fat Pads Originate from Differences in the Adipose Stem Cell

Abstract

Metabolic pathologies mainly originate from adipose tissue (AT) dysfunctions. AT differences are associated with fat-depot anatomic distribution in subcutaneous (SAT) and visceral omental (VAT) pads. We address the question whether the functional differences between the two compartments may be present early in the adipose stem cell (ASC) instead of being restricted to the mature adipocytes. Using a specific human ASC model, we evaluated proliferation/differentiation of ASC from abdominal SAT-(S-ASC) and VAT-(V-ASC) paired biopsies in parallel as well as the electrophysiological properties and functional activity of ASC and their in vitro-derived adipocytes. A dramatic difference in proliferation and adipogenic potential was observed between the two ASC populations, S-ASC having a growth rate and adipogenic potential significantly higher than V-ASC and giving rise to more functional and better organized adipocytes. To our knowledge, this is the first comprehensive electrophysiological analysis of ASC and derived-adipocytes, showing electrophysiological properties, such as membrane potential, capacitance and K+-current parameters which confirm the better functionality of S-ASC and their derived adipocytes. We document the greater ability of S-ASC-derived adipocytes to secrete adiponectin and their reduced susceptibility to lipolysis. These features may account for the metabolic differences observed between the SAT and VAT. Our findings suggest that VAT and SAT functional differences originate at the level of the adult ASC which maintains a memory of its fat pad of origin. Such stem cell differences may account for differential adipose depot susceptibility to the development of metabolic dysfunction and may represent a suitable target for specific therapeutic approaches.

Adipose morphology and metabolic disease

“…In general, across studies, SAT adipocytes were significantly larger than VAT adipocytes, irrespective of BMI or metabolic state (Liu et al, 2009;Tchernof et al, 2006), suggesting that SAT undergoes greater hypertrophy relative to VAT. However, previous studies have suggested that SAT is inherently more hyperplastic than VAT, although these observations were based on in vitro data from mouse and humans showing that SAT-derived cells have greater adipogenic capacity than VAT-derived cells (Baglioni et al, 2012;Macotela et al, 2012;Tchkonia et al, 2006). More recent in vivo data, from the transgenic AdipoChaser mouse line, have suggested the opposite: following diet-induced obesity, VAT (epidydimal) underwent waves of hyperplastic growth, whereas SAT (inguinal) did not .…”

The developmental origins of adipose tissue

“…This can be illustrated by the WNT pathway, which regulates adipose tissue formation in a spatially significant manner (Longo et al, 2004;Zeve et al, 2012). In relation to gene changes, fat-storing cells derived from subcutaneous progenitors accumulate more lipid and express higher levels of PPARγ and C/EBPα upon differentiation compared with visceral progenitor cells (Baglioni et al, 2012;Tchkonia et al, 2002). Subcutaneous progenitor cells also have improved growth rate and different electrophysiological properties (Baglioni et al, 2012;Macotela et al, 2012).…”

“…In relation to gene changes, fat-storing cells derived from subcutaneous progenitors accumulate more lipid and express higher levels of PPARγ and C/EBPα upon differentiation compared with visceral progenitor cells (Baglioni et al, 2012;Tchkonia et al, 2002). Subcutaneous progenitor cells also have improved growth rate and different electrophysiological properties (Baglioni et al, 2012;Macotela et al, 2012). Collectively, there appear to be intrinsic genetic depot-specific differences in adipose stem cells that result in different adipogenic potential, genetic expression patterns, growth rates and biological properties.…”

Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium

“…To record only K þ currents without any inward Ca 2 þ current contamination we added nifedipine (10 mM) and Ni 2 þ (50 mM) to block L-and T-type Ca 2 þ current, respectively or Cd 2 þ (0.8 mM) to block both the types. To evaluate the presence of the voltage-and Ca 2 þ -dependent delayed-rectifier iberiotoxin-sensitive K þ current (I BK ), of the slowly activating chromanol-sensitive K þ current (I Ks ) and of the fast activating α-dendrotoxin-sensitive K þ current, I K(V), we performed a pharmacological dissection as previously reported (Baglioni et al, 2012). Briefly, we first applied the stimulation protocol in control condition to record the total K þ current traces (I K,tot ).…”

“…In particular, by electrophysiological technique, we evaluated the action of melatonin on resting membrane potential and on voltage-dependent ionic channels known to play a role in proliferation (Baglioni et al, 2012;Bertolesi et al, 2002;Currò, 2014;Enomoto et al, 1986;Gamper et al, 2002;Girgert et al, 2009;Grant et al, 2009;Gray et al, 2004;Haren et al, 2010;Kunzelmann, 2005).…”