Specialty Corner: The Adipocyte: Friend or Foe?

Multicellular organisms depend on two central mechanisms for their survival: the ability to store energy to prevent starvation and the ability to fight infection. Adipocytes in higher organisms are reminiscent of the integrated function seen in lower organisms such as the fat body of the Drosophila melanogaster that comprises adipose tissue (AT), liver and immunologic cells in one unit Human adipose tissue is composed of energy-storage adipocytes as well as connective tissue matrix, vascular tissue and neural tissue. Non-adipose cells (that constitute the stromal vascular fraction include fibroblasts, pre-adipocytes and endothelial cells; leukocytes, macrophages and lymphocytes)are responsible for the chronic inflammatory response seen with obesity.¹

Energy balance is an integrated system under the regulation of the hypothalamus. Total energy expenditure (TEE) is composed of resting energy expenditure (70% of TEE), energy expended in physical activity (20% of TEE); and the Thermic Effect of Food, (10% of TEE). Adipose tissue is the largest storage body of energy. The average 70kg man has 13,000 grams of adipose tissue supplying an energy source of 120,000 kcal from the triglycerides stored in his adipocytes. Lipogenesis from glucose makes only a limited contribution to triglycerides stored in adipocytes. Chylomicrons from the diet and very lowdensity lipoproteins (VLDL) from the liver are the major sources of triglycerides for lipogenesis in the adipocyte. Lipoprotein lipase (LPL), which is manufactured in the adipocyte, hydrolyzes circulating triglycerides, releasing free fatty acids (FFAs) that are taken up by the adipocyte. Insulin and cortisol stimulate LPL activity. Lipolysis is regulated by insulin (which inhibits), and cathecolamines (which stimulate) hepatic sensitive lipase (HSL) to release FFAs from the triglycerides which are stored in adipocytes. The released FFAs, which escape immediate oxidation, are restored as triglycerides in adipose tissue, muscle or liver to provide energy during periods of famine. VLDL produced by the liver is sequentially converted to low-density lipoprotein (LDL) by LPL on endothelial cells. This releases FFAs from triglycerides to provide energy to peripheral tissues. LDL recirculates to the liver and, in times of excess, diffuses into the intima. This serves as a nidus for foam cell formation ultimately developing into an atherosclerotic plaque. In contrast to the tight negative feedback regulation of insulin secretion by glucose levels, insulin and cathecolamines concentrations are not under negative feedback regulated by lipolysis or FFA levels.²

Hypothalamic control of energy homeostasis stems from the ability of the hypothalamic neurons to orchestrate behavioral and autonomic responses. The hypothalamus receives sensory inputs from the environment, from afferent vagal neurons from the gut and from several hormones such as leptin* coming from the adipocyte and ghrelin coming from the stomach. This finely balanced system can be adversely influenced by learned behavior, emotions and personal gratification.³

Subcutaneous fat (SCAT) accumulation is the normal physiologic buffer for excess energy intake. When the ability to generate new adipocytes is impaired, because of either genetic predisposition or stresses, fat begins to spill over from the SCAT and accumulates in areas outside subcutaneous tissue. These areas include visceral adipocytes (VAT), epicardial, perivascular and myocardial cell sites. Hypertrophic adipocytes and VAT are dysfunctional and they exhibit abnormal physiology. Besides energy storage, the adipocyte produces a laundry list of hormones, cytokines, extracellular matrix proteins, complement factors, enzymes, plasminogen activator inhibitor-1 and acute- phase response proteins.⁴

Adipose tissue resident inflammatory immune cells exert a wide range of functions. They can be divided into two groups: 1) Immune cells that drive AT inflammation and insulin resistance, and 2) immune cells that protect against these pathologies. The first group consists of M1 macrophages, mast cells, B-2 cells, CD8+ T cells, and Th 1 CD4+ T cells. These cells induce the polarization of M1 macrophages and drive what is referred to as a T helper 1 (Th1) response, necessary for an efficient immune response against bacteria. The second group compromises M2 macrophages, eosinophils and regulatory T cells, which produce IL-10, IL-4 or IL-13 and drive what is referred to as a T helper 2 (Th2) response. This is instrumental for an efficient immune response against parasites. Taken together, an antibacterial Th1 response in AT is associated with inflammation and insulin resistance, while a Th2 immune cell response offers protection against parasites and in adipose tissue is anti-inflammatory and promotes insulin sensitivity.¹

Chawla and co-workers proposed a model to explain the link between metabolism and immunity that seems to help explain some of the metabolic dysfunction seen with obesity.⁵ Bacterial infections stimulate a Th1 response creating an acute bioenergetics demand because macrophages and T cells utilize circulating nutrients for an effective response to clear the bacteria. The Th1- activated immune response promotes inflammation and insulin resistance. This leads to mobilization of nutrients via gluconeogenesis, hyperglycemia and lipolysis. However, the bioenergetics for controlling parasitic infections requires the opposite response of bacterial infections. Deprivation of circulating nutrients is necessary to prevent the parasitic consumption of host nutrients and slows down parasite growth. The Th2 response in AT prevents inflammation and insulin resistance and preserves host nutrient requirements. The "energy-on-demand model" presents the Th1 and Th2 responses in AT as an adaptive strategy, allowing the body to tailor the necessary energy for the different immune responses against bacteria and parasites.¹

The lean adipocyte secretes IL-4, IL- 13, IL-10 and adiponectin** which can promote a Th 2 response of insulin sensitivity, suppressed inflammation and energy preservation. The hypertrophic adipocyte in visceral adipose tissue develops hypoxemia, oxidative stress, and endoplasmic reticulum stress. This leads to adipocyte dysfunction, inflammation and insulin resistance. The release of TNFα (Tumor Necrosis Factor alpha) from the adipocyte results in adipocyte apoptosis, which in turn promotes recruitment of lymphocytes (adaptive immunity) and macrophages (innate immunity) that surround the necrotic debris and forms crown-like structures (CLS). The lymphocytes (Th1CD4+T cells and CD8+ T cells) release IFN-γ(interferon gamma), which polarizes macrophages to a proinflammatory M1 phenotype. Saturated fatty acids and cholesterol crystals from the local environment, and gut derived lipopolysaccharides trigger TLR4 ( toll like receptor) and NLrp (Nod like receptor)³ inflammasome activation, which further promotes macrophage pro inflammatory cytokine release including IL-1β, IL-6, TNF-α and IL-18 all contributing to insulin resistance. B-2 lymphocytes respond to T-dependent antigens and influence other T lymphocytes and produce pathogenic IgG, further stimulating M1 macrophages⁶ (Please refer to figure 2).

VLDL manufactured in the liver along with chylomicrons manufactured in the gut provide energy to peripheral tissues by LPL release of FFA from triglycerides. During times of excess energy, triglycerides are stored in SCAT for release during periods of famine to provide energy to the peripheral tissues. This efficient system designed to handle the cycle of feast and famine in past times is dysfunctional in modern times of easy access to food. This leads to the development of chronic disease. It is useful to remember that except during sleep, it would be unusual to go more than 4 hours without eating. Spillover of energy storage from the SCAT to the VAT leads to dysfunctional hypertrophic adipocytes that release inflammatory cytokines, which contribute to the development of insulin resistance. An immune system designed to combat bacterial infection (Th1) is constantly activated by inflammatory cytokines released from hypertrophic adipocytes and apoptotic adipocytes in VAT. The state of persistent inflammation contributes to the development of vascular and other chronic disease (Please refer to Figure 1).

The Adipocyte and lipoproteins are essential to maintain energy homeostasis during times of feast and famine. However, in present society there is only feast and no famine. This excess of energy which needs to be stored in the adipocyte leads to insulin resistance and chronic VAT inflammation.

*Leptin’s primary role is to serve as a metabolic signal of energy sufficiency. Several other endocrine effects of leptin include regulation of immune function, hematopoiesis, angiogenesis and bone development.

** Adiponectin is the most abundant secretory protein produced by adipocytes. There is an inverse relationship between both insulin resistance and inflammation and adiponectin levels. Adiponectin levels decrease in non-human primates before the onset of obesity and insulin resistance, and suggesting that hypoadiponectinemia may contribute to the pathogenesis of these conditions.

Disclosure statement: Dr. Goldenberg has received speaker honoraria from Amarin, Abbott Laboratories, GlaxoSmithKline and Merck & Co., Inc Dr. Bathina has no disclosures to report.