Adipose Tissue: A Metabolic Regulator. Potential Implications for the Metabolic Outcome of Subjects Born Small for Gestational Age (SGA)

Abstract

Adipose tissue is involved in the regulation of glucose and lipid metabolism, energy balance, inflammation and immune response. Abdominal obesity plays a key role in the development of insulin resistance because of the high lipolytic rate of visceral adipose tissue and its secretion of adipocytokines. Low birth weight subjects are prone to central redistribution of adipose tissue and are at high risk of developing metabolic syndrome, type 2 diabetes and cardiovascular disease. Intrauterine adipogenesis may play a key role in the fetal origin of the pathogenesis of metabolic syndrome, type 2 diabetes and cardiovascular disease. Therefore, knowledge of the behavior of visceral adipose tissue-derived stem cells could provide a greater understanding of the metabolic risk related to intrauterine growth retardation, with potential clinical implications for the prevention of long-term metabolic alterations.

Figure 1

Action of adipocyte-derived free fatty acids (FFA) on glucose homeostasis. FFAs induce muscle insulin resistance by inhibiting insulin-mediated glucose uptake, and hepatic insulin resistance by affecting insulin-mediated suppression of hepatic glucose output. Chronic exposure to FFAs impairs insulin secretion from β-cells and, in the adipose tissue, reduces insulin-mediated glucose uptake and increases lipolysis. Modified from [44].

Figure 2

FFA action on liver (A), muscle (B) and β-cells (C). A: In the liver, FFAs increase lipid oxidation and accumulation of acetyl CoA. Acetyl CoA stimulates the rate-limiting enzymes for gluconeogenesis eventually leading to increased glucose output. Finally, elevated plasma FFAs inhibit the insulin signal transduction system [24, 113, 114]. B: In muscle, FFAs reduce glucose oxidation by affecting the redox potential of myocytes and inhibiting key glycolytic enzymes. Furthermore, FFAs increase IRS-1 serine phosphorylation, through activation of protein kinase C, thus inhibiting insulin signaling. Finally, ceramide accumulation interferes with glucose transport and inhibits glycogen synthesis via inhibition of protein kinase B [24, 115-117]. C: In the pancreas, lipotoxicity is an important cause of β-cell dysfunction [18, 24, 118]. If short-term elevation (e.g. after a meal) of plasma FFAs enhances insulin secretion [119], long term exposure to FFAs (>48 hours) impairs insulin secretion and eventually leads to β-cells apoptosis [120, 121]. Increased formation of ceramides from accumulated acetyl CoA augments the nitric oxide formation that causes apoptosis of β-cells [118]. This has been demonstrated in vitro in human β-cells incubated with FFAs [122], and in vivo in rodents [123]. FFA: free fatty acids. IR: insulin receptor. PEPCK: phosphoenolpyruvate carboxyl kinase. G6PD: glucose-6-phosphatase. NO: nitric oxide. Acetyl CoA: acetyl coenzyme A. PKB/Akt: protein kinase B. IRS-1: insulin receptor substrate-1. MMP: mitochondrial membrane potential.

Figure 3. Central and peripheral actions of leptin

In the hypothalamus, leptin activates neurons located in the arcuate nucleus which express the neuropeptide precursor proopiomelanocortin (POMC) leading to a reduction in food intake and increased energy expenditure [124]. The inhibition of food intake is due to the repression of orexigenic pathways such as neuropeptide Y (NPY) and agouti-related peptide (AgRP), and the activation of anorexigenic pathways such as proopiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART). The food intake-suppressing effects of leptin could be exerted through melanocortin MC4 receptor signaling, by oxytocin neurons which project from the paraventricular nucleus of the hypothalamus into the nucleus of the solitary tract [44, 125]. In muscle, leptin activates 5’AMP-activated protein kinase (AMPK) both directly and indirectly through the activation of hypothalamic-sympathetic axis [126]. AMPK inhibits acetyl CoA carboxilase-1 (ACC1), a key enzyme of the de novo fatty acids synthesis. The inhibition of ACC1 leads to reduced intracellular levels of malonyl CoA [3], the major substrate for long chain fatty acid synthesis that also suppresses fatty acid oxidation by inhibiting carnitine palmitoyltransferase (CPT-1) and acts as a signal molecule in appetite regulation [127-129]. Thereafter, fatty acids are allowed to enter the mitochondria where they undergo β oxidation [3]. Ultimately, leptin promotes fatty acid oxidation and reduces ectopic fat accumulation in non-fat tissues, increasing insulin sensitivity [3, 130]. Finally, the suppressive effect of leptin on insulin production is mediated by both the autonomic nervous system and direct actions via leptin receptor on β-cells [44].

Figure 4. The adipo-insular axis

The effect of leptin on insulin levels is due to the inhibition of proinsulin synthesis by both central actions and direct actions on β-cells [45]. In turn, insulin plays a crucial role in the regulation of leptin gene expression in white adipose tissue. A candidate transcription factor, adipocyte determination- and differentiation-dependent factor 1/sterol regulatory element binding protein 1 (ADD1/SREBP1), links changes in insulin levels to ob gene expression in mice [131]. ADD1/SREBP1 expression increases after treatment with insulin and transactivates the leptin gene. Conversely, as fat stores increase, rising plasma leptin concentrations would reduce insulin levels, diminishing the formation of adipose tissue.

Figure 5. Adipocytic differentiation of adipose-derived stem cells

Cells grown in adipogenic medium after two weeks assume a rounded shape and lipidic droplets in the cytosol that stained positively with Oil-Red-O, lipid dye.