Impaired adipose tissue expandability and lipogenic capacities as ones of the main causes of metabolic disorders

Abstract

Obesity is considered a major health problem. However, mechanisms involved and its comorbidities are not elucidated. Recent theories concerning the causes of obesity have focused on a limit to the functional capacity of adipose tissue, comparing it with other vital organs. This assumption has been the central point of interest in our laboratory. We proposed that the failure of adipose tissue is initiated by the difficulty of this tissue to increase its cellularity due to excess in fat contribution, owing to genetic or environmental factors. Nevertheless, why the adipose tissue reduces its capacity to make new adipocytes via mesenchymal cells of the stroma has not yet been elucidated. Thus, we suggest that this tissue ceases fulfilling its main function, the storage of excess fat, thereby affecting some of the key factors involved in lipogenesis, some of which are reviewed in this paper (PPARγ, ROR1, FASN, SCD1, Rab18, BrCa1, ZAG, and FABP4). On the other hand, mechanisms involved in adipose tissue expandability are also impaired, predominating hypertrophy via an increase in apoptosis and a decrease in adipogenesis and angiogenesis. However, adipose tissue failure is only part of this great orchestra, only a chapter of this nightmare.

Figure 1

Lipogenic pathway in obese patients. The loss of the lipogenic capacity of the adipose tissue is compensated by other tissues and organs, mainly the liver. Thus, many molecules come into play in this loss of lipogenic capacity of the adipose tissue, acting in a wrong way. HFD: high fat diet; IR: insulin resistance; TAG: triacylglycerol; PPARγ: peroxisome proliferator-activated receptor-γ; FASN: fatty acid synthase; ZAG: zinc-α2 glycoprotein; FABP4: fatty acid-binding protein 4; RORγ1: retinoic acid receptor-related orphan nuclear receptor γ1; SCD1: stearoyl-CoA desaturase-1; Rab18: Ras-related protein 18; BrCa1: breast cancer 1.

Figure 2

The adipose tissue expansion is produced via hypertrophy in a first point. If the surplus of energy continues, adipose tissue expansion will happen via hyperplasia and/or hypertrophy. In these mechanisms, different mechanisms intervene: adipogenesis, apoptosis, and/or angiogenesis, which will determine the metabolic status of the patient. Moreover, within each mechanism, this adipose tissue can be modulated. HFD: high fat diet; SFRP1: secreted frizzled-related protein 1; S14: thyroid hormone responsive Spot 14; VEGF-A/B/C/D: vascular endothelial growth factor A/B/C/D; TWEAK: TNF-like weak inducer of apoptosis; CASP3/7: Caspasas3/7; BCL2: B-cell lymphoma 2; TRAIL: TNF (tumor necrosis factor)-related apoptosis-inducing ligand.

Figure 3

Secreted frizzled-related protein 1 (SFRP1) upregulation in early stages of obesity facilitates adipose tissue expansion, falling in morbidly obese patients [77].

Figure 4

Fat accumulation leads to a high number of commorbidities associated to the metabolic syndrome. Many factors intervene in this situation. Many of them are known but not understood, many are even unknown, so research must be continue until we can elucidate how this great orchestra sounds in the right way.