Abstract
The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor cells. When inadequate, this leads to a hypertrophic expansion of the cells with increased inflammation, insulin resistance, and a dysfunctional prolipolytic tissue. Epi-/genetic factors regulate SAT adipogenesis and genetic predisposition for type 2 diabetes is associated with markers of an impaired SAT adipogenesis and development of hypertrophic obesity also in nonobese individuals. We here review mechanisms for the adipose precursor cells to enter adipogenesis, emphasizing the role of bone morphogenetic protein-4 (BMP-4) and its endogenous antagonist gremlin-1, which is increased in hypertrophic SAT in humans. Gremlin-1 is a secreted and a likely important mechanism for the impaired SAT adipogenesis in hypertrophic obesity. Transiently increasing BMP-4 enhances adipogenic commitment of the precursor cells while maintained BMP-4 signaling during differentiation induces a beige/brown oxidative phenotype in both human and murine adipose cells. Adipose tissue growth and development also requires increased angiogenesis, and BMP-4, as a proangiogenic molecule, may also be an important feedback regulator of this. Hypertrophic obesity is also associated with increased lipolysis. Reduced lipid storage and increased release of FFA by hypertrophic SAT are important mechanisms for the accumulation of ectopic fat in the liver and other places promoting insulin resistance. Taken together, the limited expansion and storage capacity of SAT is a major driver of the obesity-associated metabolic complications.
Highlights
The adipose tissue is a good example of the concept that both too much and too little can be harmful! the metabolic complications of both too much adipose tissue and too little are quite similar and increase the risk of type 2 diabetes (T2D), liver disease, cardiovascular disease (CVD), certain cancers, and other disorders
When the limited storage capacity of subcutaneous adipose tissue (SAT) is exceeded in obesity, excess lipids accumulate in both the visceral depot as well as in the ectopic sites, promoting the same metabolic and other consequences
SAT is characterized by hypertrophic adipose cells, the tissue becomes inflamed, and dysfunctional and excess lipids are stored in other more harmful adipose tissue depots and in ectopic sites
Summary
The adipose tissue is a good example of the concept that both too much and too little can be harmful! the metabolic complications of both too much adipose tissue (in obesity) and too little (lipoatrophy/lipodystrophy) are quite similar and increase the risk of type 2 diabetes (T2D), liver disease, cardiovascular disease (CVD), certain cancers, and other disorders. SAT is characterized by hypertrophic adipose cells, the tissue becomes inflamed, and dysfunctional and excess lipids are stored in other more harmful adipose tissue depots (for instance visceral and peri-/epicardial fat) and in ectopic sites. Adipose cell lipolysis and FFA release are increased in obesity as a consequence of the increased amount of body fat and the hypertrophic expansion of the adipose cells, which, in turn, is associated with local and systemic insulin resistance. Adipose cell FFA release is increased since basal lipolysis is increased and the anti-lipolytic effect of insulin is reduced. The adipose tissue is a key regulator of lipid storage and release in the body, but it is an endocrine organ secreting many different hormones that cross talk with central and peripheral cells. The final part of this review is focused on the consequences of a dysfunctional adipose tissue, reviewing the current knowledge on ectopic lipid accumulation, its effects in peripheral tissues, and the metabolic consequences
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