Research Progress Of Testosterone And Hyperlipidemia, Energy Metabolism Imbalance And Obesity

【Abstract】 Testosterone is an essential regulatory Regulation. Its imbalance can lead to normal blood lipid metabolism, energy metabolism imbalance, and obesity.

Both male testosterone deficiency and female hyperandrogenemia are accompanied by varying degrees of dyslipidemia And energy metabolism. This article mainly discusses the effects of soft testosterone on hyperlipidemia, energy metabolism disorders, and obesity.

【Keywords】Testosterone; Hyperlipidemia; Energy metabolism imbalance; Obesity

Hyperlipidemia, energy metabolism imbalance, and obesity are common chronic diseases in today's society, and the three often appear one after another and are closely related to hypertension, coronary heart disease, stroke, and other metabolic disorders [1]. A variety of factors such as diet and genetics can affect its occurrence and progression, and testosterone has also been found to be related to its disease. A number of epidemiological studies have shown that testosterone levels are significantly negatively correlated with obesity, and the correlation between the two is independent of the impact of metabolic syndrome [2]. A retrospective study of 2906 Argentine men (45-70 years old) with prostate cancer found that total testosterone levels were inversely associated with body mass index, waist circumference, fasting blood glucose and triglycerides (TG), and were associated with high-density lipoprotein cholesterol ( HDL-C) was positively correlated [3]. Testosterone is a steroid hormone synthesized in the gonads and adrenal glands and is an androgen receptor agonist. The androgen receptor is a nuclear receptor, and upon binding to its ligand, the androgen receptor is released, homodimerized, phosphorylated, and translocated into the nucleus, where it attaches to target DNA, thereby recruiting a series of transcriptional activators Or repressors, affecting the expression of the target gene [4]. Testosterone regulates body composition, erythropoiesis, and osteoporosis, and is involved in the regulation of fatty acid metabolism, blood sugar regulation, and energy homeostasis. Testosterone deficiency can be manifested as decreased muscle mass and strength, abnormal blood glucose and lipid metabolism, increased visceral fat mass, osteoporosis, lethargy, lack of energy and mood changes [5].

This review focuses on the effects of testosterone and androgen signaling on hyperlipidemia, energy metabolism disorders, and obesity.

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1 Testosterone and hyperlipidemia

1.1 Epidemiological evidence

Hyperlipidemia refers to high serum levels of TG, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and low levels of HDL-C. In the United States, the prevalence of low HDL-C in adult men is three times higher than in women. The TC levels of young and middle-aged men and women were similar [6]. However, for adults aged 60 years and older, the prevalence of high TC in women was 2.5 times higher than in men. Several cross-sectional studies targeting different populations at home and abroad have shown that male total testosterone levels are negatively correlated with TC, TG and LDL-C, and positively correlated with HDL-C [7,8]. Serum TC and LDL-C levels were significantly reduced after testosterone replacement therapy in hypogonadal male patients [9]. At the same time, lipoprotein a [Lp(a)], which is independently associated with coronary heart disease, was also found to be significantly decreased after testosterone replacement therapy [10]. These findings suggest that low testosterone levels in men are associated with abnormal lipid metabolism.

1.2 Molecular mechanism

1.2.1 The effect of testosterone on cholesterol metabolism:

The molecular mechanisms underlying the effects of testosterone on cholesterol metabolism are unknown. Studies have shown that the regulation of cholesterol metabolism by testosterone may be related to the changes of scavenger receptor B1 (SR-B1) and hepatic lipase. The phospholipids on the surface of HDL-C promote the selective uptake of HDL-C by SR-B1, thereby promoting the reverse transport of cholesterol to play an anti-atherosclerotic effect [11]. In addition, a study targeting testosterone deficiency and changes in porcine cholesterol metabolism

A variable study found that testosterone deficiency caused a decrease in the expression of low-density lipoprotein receptor (LDLR) mRNA in the liver of pigs. LDLR is an important regulator of serum LDL-C levels in humans and animals, and a decrease in LDLR expression level will lead to an increase in serum LDL-C levels. At the same time, in the liver of testosterone-deficient pigs, it was also observed

The expression level of PCSK9 was increased. PCSK9 can regulate cholesterol metabolism by enhancing the degradation of hepatic LDLR, resulting in an increase in serum LDL-C concentration [12].

1.2.2 The effect of testosterone on TG metabolism:

TG in the liver is packaged as very low density lipoprotein (VLDL) and enters the circulatory system. Excessive production of TG-rich VLDL (VLDL-TG) can lead to hyperTGemia. Many genes are involved in the assembly and secretion of VLDL-TG, such as microsomal TG transfer protein (MTP) and apolipoprotein AV (ApoA-V). level [13]. Studies have found that testosterone can regulate the expression of MTP in the liver of rats and mice, and the lack of testosterone can lead to a decrease in the expression of MTP [14]. Recent studies have shown that ApoA-V expression is reduced in obese subjects. In addition, treatment of HepG2 cells with insulin decreased the expression of ApoA-V [15]. Testosterone deficiency is associated with obesity and insulin resistance. Therefore, testosterone deficiency may affect serum TG levels by altering the expression of genes involved in lipoprotein assembly and secretion.

2 The effect of testosterone on energy metabolism

2.1 Epidemiological evidence

Testosterone can affect the homeostasis of energy metabolism by regulating the metabolism of sugar, protein and fat, thereby affecting the occurrence and progression of various metabolic diseases such as diabetes, obesity and metabolic syndrome. In a meta-analysis of 28 cross-sectional and prospective studies, Ding et al. [16] found that sugar

Total testosterone levels in men with diabetes were consistently lower than in non-diabetic controls, and higher testosterone levels were associated with a lower risk of developing diabetes.

Furthermore, the same meta-analysis of the metabolic effects of testosterone replacement therapy found that testosterone therapy was associated with a significant reduction in fasting blood glucose, glycated hemoglobin, fat mass, and TG in men [17]. Corona et al [18] found that testosterone replacement therapy can improve central obesity and glucose metabolism disorders in patients with metabolic syndrome and type 2 diabetes.

2.2 Molecular mechanism

2.2.1 The effect of testosterone on glucose metabolism:

Insulin is an important regulator to maintain the balance of glucose metabolism, and testosterone deficiency is associated with insulin resistance.

happens about. Testosterone acts primarily by binding to androgen receptors, and a study of male mice deficient in pancreatic beta-cell androgen receptors found that androgen signaling works by amplifying glucagon-like peptide-1 incretin effect to enhance glucose-stimulated insulin secretion in β cells [19]. Insulin resistance caused by testosterone deficiency results in decreased muscle glucose uptake and decreased hepatic glycogen synthesis, which in turn leads to disorders of glucose metabolism.

2.2.2 The effect of testosterone on protein metabolism:

The amino acids produced by proteolysis are mainly used for synthesis into new proteins, replacing whole-body protein approximately every 160 days [20]. About 20% of amino acids are lost during oxidation, which is an irreversible loss of protein and is a hallmark of catabolism. Testosterone can reduce the rate of protein oxidation and promote the reuse of amino acids, thereby promoting the increase of muscle protein, thereby promoting the increase of muscle mass [21]. Studies have found that there is a certain correlation between male serum testosterone levels and muscle mass [22]. Testosterone deficiency can lead to a decrease in muscle mass in middle-aged and elderly men [23].

Lean body mass is the most important determinant of resting energy expenditure. The amount of muscle mass is related to lean body mass. The decrease in muscle mass caused by testosterone deficiency is related to the decrease in resting energy expenditure [24].

2.2.3 The effect of testosterone on fat metabolism:

Leptin is an important regulator that affects fat metabolism, and testosterone can affect the regulation of lipid metabolism by leptin by binding to androgen receptors. The androgen receptor is highly expressed in various hypothalamic nuclei, which also express the long-form leptin receptor. In androgen receptor-deficient male mice, leptin fails to promote nuclear localization of activator of transcription 3 (STAT3) in arcuate nucleus neurons, resulting in increased food intake, which in the presence of obesity will not be suppressed [25]. A study of male mice deficient in systemic androgen receptors found that in the absence of increased energy intake, such mice developed obesity, which was associated with reduced exercise activity and lower energy expenditure. At the same time, these mice also showed reduced brown adipose tissue heat production, resulting in reduced energy expenditure [26].

3 Testosterone and obesity

3.1 Bidirectional relationship between testosterone and obesity

The impact of testosterone deficiency on visceral obesity, insulin resistance, and the development of metabolic syndrome in men is well established. Growing evidence suggests an inverse association between testosterone and obesity, but the causal relationship between the two remains controversial. An increase in the amount of visceral adipose tissue has been observed in patients with testosterone deficiency, including hypogonadism in older men, hereditary testosterone deficiency in Klinefelter syndrome, and androgen deficiency during prostate cancer treatment, suggesting that testosterone deficiency is a function of obesity. reasons [27, 28]. However, evidence from meta-analyses suggests that weight loss resulting from diet, exercise, or bariatric surgery can significantly increase testosterone levels in men, suggesting that in this relationship, low testosterone may simply be a consequence of obesity [29]. Currently, the most common view is that the relationship between low testosterone and obesity is bidirectional.

3.2 The effect of obesity on serum testosterone levels

Fat cells highly express aromatase, which promotes the conversion of testosterone to estradiol, thereby reducing circulating testosterone levels. At the same time, estrogen can act on the hypothalamic-pituitary axis, thereby inhibiting the release of gonadotropin-releasing hormone (GnRH) and subsequent luteinizing hormone (LH), and ultimately leading to a decrease in testosterone release [30]. Therefore, obesity directly affects testosterone levels. In addition to the inhibition of the hypothalamic-pituitary axis by estrogen, inflammatory factors secreted by adipocytes, such as tumor necrosis factor α and interleukin-6, also have similar inhibitory effects, which can inhibit the secretion of GnRH in the hypothalamus. In contrast, leptin, an adipose-derived hormone that regulates body weight and food intake, also stimulates GnRH neurons in the hypothalamus to induce LH release, which in turn regulates testosterone secretion. However, in obese patients, weight gain can lead to a substantial increase in leptin levels, which in turn induces leptin resistance in the hypothalamus, resulting in diminished feedback stimulation of testosterone production [31].

3.3 The effect of testosterone on adipose tissue

3.3.1 Regulation of testosterone on lipid uptake: Lipoprotein lipase (LPL) is an important enzyme involved in lipid uptake, and its abnormal activity is related to the pathogenesis of obesity. LPL resides on the extracellular surface of adipocytes and hydrolyzes circulating TG-rich lipoproteins into fatty acids, which are absorbed into adipocytes and then esterified back to TG for storage [32]. Abdominal adipose tissue LPL activity was significantly negatively correlated with plasma bioavailable testosterone levels in obese men. Therapeutic doses of testosterone can significantly reduce LPL activity in abdominal adipose tissue in middle-aged men within 6 weeks [33]. A long-term treatment study showed that 9 months of testosterone replacement therapy in hypogonadal men reduced LPL activity and TG uptake in subcutaneous abdominal adipose tissue [34].

3.3.2 Regulation of testosterone on lipid breakdown:

Multiple in vitro and in vivo studies have shown that testosterone can regulate lipid catabolism. Studies have found that basal fat breakdown is reduced in male hamsters after castration [35]. Studies in adipocytes isolated from normal male rats have shown that testosterone enhances norepinephrine-stimulated lipolysis, a mechanism that may be related to an increase in the number of β-adrenergic receptors [36]. In androgen receptor-deficient mice, it was found that the decreased ability of androgen-induced lipolysis is the main cause of increased visceral fat and delayed obesity [37].

3.3.3 Regulation of testosterone on adipogenesis:

Adipogenesis refers to the process by which mesenchymal progenitor cells differentiate into mature adipocytes. testosterone inhibits

Influence the adipogenesis process by controlling the differentiation and formation of new adipocytes. In cultured pluripotent murine stem cells, Singh et al. [38] demonstrated that testosterone stimulates the development of myocyte lineage cells but not adipocytes, and that testosterone deficiency promotes adipocyte development. This effect on differentiation was accompanied by decreased expression of peroxisome proliferator-activated receptor gamma (PPARγ), a signaling molecule known to regulate adipogenic dimorphism and lipid metabolism [39]. In addition, androgens also regulate the transcription of several noncoding microRNAs involved in post-transcriptional gene regulation, thereby affecting adipogenesis. in several items

In studies, androgen-induced up-regulation of miR-21 can be observed, and the up-regulation of miR-21 can promote the transformation of mesenchymal stem cells into adipocytes by regulating the ERK-MAPK4 pathway [40].

4 Summary and Outlook

Hyperlipidemia, energy metabolism imbalance, and obesity are high incidences of metabolic diseases in today's society, and these diseases are often accompanied by more serious cardiovascular diseases and endocrine disorders. At present, the reasons for abnormal lipid and energy metabolism are not fully understood, but more and more evidence shows that testosterone can regulate blood lipid metabolism, energy homeostasis, and the occurrence and progression of obesity. Testosterone replacement therapy has been found to regulate body fat distribution to some extent and prevent obesity and cardiovascular disease. However, there is still controversy about testosterone replacement therapy. Therefore, understanding the regulation mechanism of testosterone on lipids and energy is more helpful for the clinical practice of testosterone replacement therapy.

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