Abstract

Perirenal adipose tissue, one of the fat masses surrounding the kidneys, can be obtained from healthy donors during a kidney transplant. Perirenal adipose tissue has only ever been known as a connective tissue to protect the kidneys and renal blood vessels from external physical stimulation. Yet, recently, adipose tissue has begun to be considered an endocrine organ, and perirenal adipose tissue is now regarded to have a direct effect on metabolic diseases. The characteristics of perirenal adipose tissue from a healthy donor are that: (Ⅰ) There are a large number of brown adipose cells (70–80% of the total), (Ⅱ) Most of the brown adipose cells are inactive in the resting cell cycle, (Ⅲ) Activating factors are constant low-temperature exposure, hormones, metastasis factors, and environmental factors, (Ⅳ) Anatomically, a large number of brown adipose cells are distributed close to the adrenal glands, (Ⅴ) Beige cells, produced by converting white adipocytes to brown-like adipocytes, are highly active, (Ⅵ) Activated cells secrete BATokines, and (Ⅶ) Energy consumption efficiency is high. Despite these advantages, all of the perirenal adipose tissue from a healthy donor is incinerated as medical waste. With a view to its use, this review discusses the brown adipocytes and beige cells in perirenal adipose tissue from a healthy donor and proposes opportunities for their clinical application.

Keywords

perirenal; adipose tissue; healthy donor; brown adipocytes; beige cells; Cistanche extract benefits

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Perirenal Adipose Tissue

There are three types of fat surrounding the kidney: pararenal fat, sinus fat, and perirenal fat. The pararenal fat is located outside the renal membrane and consists of white fat [1]. The renal sinus fat is distributed around the renal vessels, is present within the renal membrane, and increases with obesity. The perirenal fat is located in the retroperitoneal cavity and is considered to be a simple connective tissue that protects the kidney and renal vessels from external physical stimuli (Figure 1A) [1].

Figure 1. Characterization of perirenal adipose tissue. (A) Anatomic location of perirenal adipose tissue, (B) Perirenaladipose tissue composing adipose cell types, (C) Thermogenesis of brown adipocyte for calorie burning, (D) Adipokines, secreted by brown, white, and beige adipocytes, and (E) Browning inducers for white adipocyte transformation into the beige cell.

Nevertheless, with adipose tissue being considered as an endocrine organ that secretes various adipokines and not just energy storage, perirenal adipose tissue is considered to directly affect metabolic diseases such as diabetes, obesity, and cardiovascular abnormalities [2]. As an endocrine organ, perirenal adipose tissue contains a large number of brown adipocytes [3] and highly activated beige cells generated by the transformation of white adipocytes [4]. Therefore, perirenal adipose tissue is considered to be a very useful source of cells for therapeutic purposes.

However, all perirenal adipose tissue obtained from healthy donors during renal transplantation is incinerated as medical waste. To increase the possibility of its clinical application, this article reviews the characteristics and potential applications of perirenal adipose tissue.

Adipocyte types in perirenal adipose tissue

The adipocytes that make up the perirenal adipose tissue, like other adipose tissues, are mostly divided into white cells and brown cells (Figure 1B). White adipocytes store energy in the form of triglycerides, which are broken down into fatty acids and glycerol during fasting. They influence appetite and insulin sensitivity in the same way as endocrine organs by secreting hormone-like molecules such as leptin and lipocalin. At the same time, brown adipocytes maintain body temperature by releasing chemical energy as heat through an uncoupling protein 1 (UCP1)-mediated pathway, a defense mechanism against hypothermia (Figure 1C) [6,7].

Histologically, adipocytes have a uniform shape separated by thin collagen intervals. In white adipocytes, the cytoplasm is pushed to the edge by the pressure of fat droplets. Meanwhile, the nucleus is small and thin, oval-shaped, and pushed to the side with a large fat drop in the middle (Figure 1B(b)) [8]. Brown adipocytes are smaller and contain many fat droplets (Figure 1B(a)) [3). When white adipocytes have high UCP1 expression and many small fat droplets, they are called beige cells (Figure 1B(c)) [9l.]. Beige cells are of different origin than brown adipocytes, but have the same energy-consuming function as calories; therefore, they are of clinical value.

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Benefits of Brown Adipose Tissue

The main role of brown adipose tissue is to maintain a constant body temperature by generating heat; generating 300 kcal and consuming 50 g of brown adipose tissue (Figure 1C) [10]. The calorie-burning action of brown adipose tissue can be applied in the treatment of obesity and insulin resistance, which are metabolic disorders caused by excessive energy accumulation.

When brown adipocytes are activated, glucose and fatty acids are efficiently removed from the blood; blood glucose is eliminated by activating β3-adrenergic receptors on the brown adipocyte membrane, followed by increased synthesis of glucose transporter 1 (GLUT1), a glucose transporter, by cyclic adenosine monophosphate (cAMP) in the cytoplasm [11]. Plasma triglycerides are removed by activating lipoprotein proteases and CD36 secreted by brown adipocytes [12]. Thus, activation of brown adipocytes can effectively improve insulin sensitivity and energy expenditure and reduce body weight.

Until recently, brown adipose tissue was thought to be absent in humans at all stages from infancy to adulthood. However, with the development of metabolic activity measurement devices (fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)/computed tomography (CT)), brown adipose tissue was found to be present in thermosensitive tissues in adults [13]. In particular, a large amount of brown adipose tissue was found around the kidney, which is highly active [14]. In our ongoing preliminary experiments, we retained 302 peripheral adipose tissues; the average weight of the kidney donors was 229.19 ± 136.53 g and the average age was 32.98 ± 9.94 years. Using 17 samples, we measured the distribution of brown fat and found it to be present in 10-60% (v/v) of the tissue. There were significant individual differences in the volume of brown fat.

Brown Adipose Tissue as a Heat Generator

The organelles involved in energy production are the mitochondria, and chemical and thermal energy are generated through two channels in the inner mitochondrial membrane. Protons leave the mitochondria through the electron transfer pathway, causing a potential difference; chemical energy (ATP) is generated when protons enter through the ATP synthesis complex, and thermal energy is generated when protons enter the UCP1 pathway, activating fatty acid oxidation in the mitochondria (Figure 1C) [15].

Brown fat is a special tissue that we use to adapt to the cold. When exposed to low temperatures, sympathetic nerves secrete catecholamines (especially norepinephrine), and their receptors (β3-adrenergic receptors) are activated. Then, UCP1 in the inner mitochondrial membrane is activated. Temperature-related genes in brown adipocytes are continuously active when we experience regular temperature differences, but white adipocyte-derived beige cells are activated only when we experience low-temperature exposure [16].

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Brown Adipose Tissue as an Endocrine Organ

Activated brown adipocytes secrete substances through endocrine pathways that affect other metabolic tissues (motor muscles) and regulate energy metabolism [4] and inflammation [17]. The substances secreted by brown adipose tissue are called brown adipose tissue (BAT) adipokines or BATokines and are secreted by autocrine, paracrine, peripheral, and endocrine pathways (Figure 1D) [18].

Autocrine and peripherally secreted substances are NGF, FGF2, and VEGF-A, which are involved in the growth of brown adipocytes, vascularization, neutralization, and blood flow processes; these substances play a role in activating brown adipocytes when exposed to cold environments. The substances secreted by the endocrine system are IGF1 and FGF21. IGF1 plays a role in reducing the concentration of glucose in the blood. FGF21 increases in the blood at low temperatures by activating brown adipocytes [20], participates in the browning of white adipocytes [21], and regulates energy metabolism through the lipoprotein catabolic pathway [22]. We analyzed the concentrations of NGF, FGF2, VEGF-A, IGF1, and FGF21 using 10 peripheral adipose tissues. According to the manufacturer's instructions, 25 g of each tissue was taken as the initial volume, and a stromal vascular fraction (SVF) was obtained using a manual kit (Ustem kit, Ustem Biomedical, Seoul, Korea). The final product volume was 1 mL, and NGF 3.56±0.25 pg/mL, FGF2 230.27±167.24 pg/mL, VEGF-A 7.50±5.95 pg/mL, IGF1 2830.85±5201.98 pg/mL, and FGF21 3.36±0.19 pg/mL were determined. fGF2, VEGF- A and IGF1 showed significant individual differences, while NGF and FGF21 showed relatively uniform performance.

Brown adipose tissue also plays a role in the inflammatory response. Anti-inflammatory BATokines directly secreted by brown/beige adipocytes are SLIT2-C, VEGFA, IGF-1, FGF21, CXCL14, L-PGDS, follistatin, IL6, and GDF15 [17]. In addition, when an inflammatory microenvironment develops (e.g., obesity), the infiltration of macrophages and other immune cells into adipose tissue is increased. Immune cells mainly secrete pro-inflammatory cytokines that inhibit the "white adipocyte to beige adipocyte transition" and promote the "brown adipocyte whitening". Phenotypically whitened brown adipocytes secrete pro-inflammatory BATokines such as Chemerin, IGF-1, CX3CL1, RBP4, TNFα, GDF8, ET-1, IL6, IL1, and MCP1 [17]. The whitened brown adipocytes have reduced thermogenic activity and suppressed energy expenditure capacity, thus losing the physiological efficacy of brown adipocytes.

Brown adiposity is also associated with circulating exosomal miRNAs. secretion of exosomal microRNAs by BAT represses transcription. When BAT was transplanted into mice lacking the miRNA-processing enzyme dicer, which makes microRNAs, various types of microRNAs were observed, glucose tolerance was reduced [23], and miR-92 is known to be associated with glucose uptake in brown fat [24].

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1. Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu 41405, Korea;