Extracellular Matrix Remodeling and Mechanical Stresses as Modulators of Adipose Tissue Metabolism and Inflammation - The Mechanobiology of Obesity and Related Diseases - page 105

3 Tissue Stiffening Leads to Metabolic Stress
and Inflammation

Taken together, the aforementioned studies indicate that ECM remodeling is
essential for WAT plasticity. In obese subjects, adipose expandability could be
compromised, as deposition of fibrillar ECM proteins outpaces MMP activity,
resulting in fibrosis. It remains an open question whether fibrosis acts to limit
differentiation of precursor cells into adipocytes, expansion of mature adipocytes,
or both. Regardless, the ensuing ''stiffening'' of the tissue could further contribute
to a state of metabolic stress by favoring the hydrolysis of stored TG, i.e. lipolysis,
over fatty acid esterification and storage. Normally, lipolysis is under tight hor-
monal regulation. Catecholamine stimulation activates hormone-sensitive lipase
(HSL) through a G-protein coupled receptor (GPCR)-dependent signalling cascade
mediated by protein kinase A (PKA). Insulin potently inhibits lipolysis by acti-
vating a phosphodiesterase (PDE3B) to lower the intracellular level of cAMP and
reduce PKA activity, thereby attenuating post-translational activation of HSL.
Under conditions of fibrosis and limited adipose expandability, excess free fatty
acids that cannot be stored as esterified lipids could establish a positive feedback
loop for elevated lipolysis, as the metabolite products of HSL are putative ligands
or pro-ligands for peroxisome proliferator-activated receptor-c (PPARc)[ 20 ]. The
transcription factor PPARc is a key regulator of differentiation adipocyte function
whose many metabolic targets include adipose triglyceride lipase (ATGL), a
lipolytic enzyme that acts upstream of HSL.
Experiments with isolated cells from human subcutaneous WAT showed that
both basal and hormone stimulated lipolysis positively correlates with cell size
[ 21 ]. The same study also observed higher expression of lipolytic enzymes hor-
mone sensitive lipase (HSL) and ATGL in larger adipocytes. These and other
metabolic studies on hypertrophic adipocytes suggest that increased lipolysis,
sustained over time, could overwhelm the re-esterification capacity of WAT
depots, and up-regulate net fatty acid efflux [ 22 ].
Elevation of extracellular free fatty acid levels in turn could further promote local
inflammation through a variety of signaling mechanisms involving recruitment and/
or polarization of macrophages [ 23 - 25 ]. In addition to fatty acids, the levels of
several immune cell recruitment factors are elevated in WAT of obese individuals.
An important factor linking adipose tissue inflammation with metabolic phenotypes
characteristic of obesity is the monocyte chemoattractant protein-1 (MCP-1).
Adipose-specific overexpression of MCP-1 in mice led to insulin resistance, higher
levels of free fatty acids in circulation, and greater accumulation of macrophages and
elevated expression of pro-inflammatory cytokines in WAT [ 26 ].
Almost all macrophages in adipose tissue localize to dying/dead adipocytes,
where they scavenge the residual free (extracellular) lipid droplets and fuse with
other macrophages to form multinucleate giant cells [ 27 ]. This would suggest that
adipocyte death is an early event in WAT macrophage recruitment and inflammation
[ 28 ]. However, recent studies with granulocyte/monocyte-colony stimulating