Dihydrotestosterone Treatment Results in Obesity and Altered Lipid Metabolism in Orchidectomized Mice

Movérare‐Skrtic, Sofia; Venken, Katrien; Andersson, Niklas; Lindberg, Mattias F.; Svensson, Johan; Swanson, Charlotte; Vanderschueren, Dirk; Oscarsson, Jan; Gustafsson, Jan Åke; Ohlsson, Claes

doi:10.1038/oby.2006.75

Cited by 95 publications

(81 citation statements)

References 60 publications

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“…Importantly, however, Lin et al did not measure testosterone levels in high-fat diet-fed animals and thus could not determine whether increased hepatic steatosis was due to AR function or an obesity-related testosterone decline. By contrast, hepatic Scd1 mRNA expression was increased following DHT treatment in orchidectomised obese mice compared with placebo-treated controls (Movérare-Skrtic et al 2006). Significantly elevated Scd1 expression also remained when compared to sham-operated controls, suggesting possible pharmacological effects of DHT administration.…”

Section: Livermentioning

confidence: 65%

“…At the same time, microsomal triglyceride transfer protein was decreased by DHT, thus reducing apolipoprotein B-mediated very LDL (VLDL) secretion. Cholesterol 7a-hydroxylase, a key enzyme in bile acid formation and therefore removal of cholesterol from the body, was decreased following DHT administration in this study, leading to hepatic lipid accumulation due to increased cholesterol uptake but decreased removal (Movérare-Skrtic et al 2006). Contrariwise, AR-independent effects on hepatic steatosis and lipid metabolism have been demonstrated in the Tfm mouse (Kelly et al 2012).…”

Section: Livermentioning

confidence: 71%

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Testosterone: a metabolic hormone in health and disease

Kelly

Jones

2013

Journal of Endocrinology

423

330

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Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials. This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement.

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Section: Livermentioning

confidence: 65%

Section: Livermentioning

confidence: 71%

Testosterone: a metabolic hormone in health and disease

Kelly

Jones

2013

Journal of Endocrinology

423

330

View full text Add to dashboard Cite

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“…Indeed, administration of gens such as testosterone in older me and abdominal fat and increases whereas in vivo and in vitro studies s play a significant role in altering fa distribution [50][51][52][53]. ARs are found in more being present in visceral compa depots [54].…”

Section: Neuroendocrine Control Of Bone and Fatmentioning

confidence: 99%

Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat

Zengin

Zhang

Herzog

et al. 2010

Trends in Endocrinology & Metabolism

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The hypothalamus regulates the skeleton and adipose tissue via endocrine mechanisms. Changes in sex steroid levels in menopause and aging are central to the associated changes in bone mass and adiposity. Whereas many of these effects occur via direct actions on osteoblasts or adipocytes, sex hormones can also mediate effects on bone and adipose tissue via interaction with neuronal pathways. A key hypothalamic regulator of bone and adipose tissue is neuropeptide Y (NPY), which coordinately influences these tissues via effects on neuroendocrine and sympathetic nervous output. Better understanding of the interaction between NPY and sex steroids in regulating skeletal and energy homeostasis could lead to more effective treatments for osteoporosis and obesity. Neuroendocrine control of bone and fatOsteoporosis and excess central adiposity, increasingly prevalent in ageing populations, increase the risk of fractures and diseases such as type-2 diabetes mellitus, and adversely affect both quality of life and survival. The regulation of bone and adipose tissue mass has traditionally been studied independently, but osteoblasts and adipocytes are derived from the same mesenchymal precursor cells, and recent findings that the bone-or fat-derived hormones, osteocalcin and leptin, have significant effects on energy homeostasis and bone [1], respectively, now suggest that bone and adipose tissue share common regulatory pathways. The hypothalamus acts as a pivotal regulator of homeostasis in bone and adipose tissue via regulation of hypothalamopituitary axes. For instance, activation of the hypothalamo-pituitary-adrenal axis, or inhibition of the hypothalamo-pituitary-somatotropic or -gonadotropic axes (as in stress or negative energy balance), can affect circulating concentrations of cortisol, insulin like growth factor-1 (IGF-1) and sex steroids that inhibit bone formation while promoting conservation of fat mass, particularly central adiposity 2, 3 and 4. Sex hormones -a major focus of this review -influence bone and fat via direct actions on osteoblasts or adipocytes 2, 3, 5, 6, 7 and 8. Recently, however, it has been recognized that sex hormones can influence these tissues via the neuropeptide Y (NPY) system (Box 1) 9, 10, 11 and 12, that also regulates bone and adipocyte homeostasis via actions in the hypothalamus and peripheral tissues 9, 13 and 14. In this review we examine the role of sex hormones in skeletal and energy homeostasis, with particular focus on their interaction with NPY. Whereas research into the isolated effects of sex hormones or the NPY system on bone and adipose tissue homeostasis has led to identification of potential novel drug targets for the treatment of osteoporosis or central obesity, emerging research into the interaction of these systems could pave the way for even better treatments for these conditions, particularly in the context of reduced circulating concentrations of sex hormones, as in menopause or ageing in women and in men. Zenging et al.: Trends in Endocrinology & Metabolism, 2(7): 4...

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“…The 3.0 mg/kg/d dosage of DHT was chosen because it was shown that this dosage can restore the weight of the ventral prostate (VP) in ORX rats (control: 0.062 ± 0.13 g/VP; ORX: 0.02 ± 0.01 g/VP; DHT: 0.070 ± 0.32 g/VP). The 1.0 mg/kg/d dosage of E2 was chosen because this dosage was shown to prevent ORX-induced trabecular bone loss (Moverate-Skrtic et al, 25 ). Subcutaneous injections were given to all animals at the same time (16:00 h).…”

mentioning

confidence: 99%

Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat

Zhang

Liu

Wang

et al. 2013

Journal of Lipid Research

123

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Nonalcoholic fatty liver disease (NAFLD) is strongly linked to central obesity, insulin resistance (IR), and metabolic syndrome ( 1 ), and its increasing prevalence is estimated at 20-30% among the adult population in industrialized countries ( 2 ).Although estrogen and androgen are important regulators of lipid homeostasis ( 3, 4 ), data on their possible infl uence on the prevention or treatment of NAFLD are scarce. Clinically, tamoxifen (Tam) is widely used for the treatment of estrogen-responsive breast cancer, but its frequent side effect is the development of NAFLD. Forty-three percent of patients with Tam-treated breast cancer develop steatosis Abstract It is important to clarify the distinct contributions of estrogen/estrogen receptor (ER) and androgen/androgen receptor (AR) signaling and their reciprocal effects on the regulation of hepatic lipid homeostasis. We studied the molecular mechanisms underlying the preventive effects of estradiol (E2), dihydrotestosterone (DHT), or E2+DHT on high-fat diet-induced nonalcoholic fatty liver disease (NAFLD) in an orchidectomized Sprague-Dawley (SD) rat model. E2 is shown to be associated with decreased fatty acid synthesis in hepatic zone 3-specifi c manner by increasing the phosphorylation of acetyl coenzyme-A carboxylase via an ER ␣ -mediated pathway. DHT is shown to be associated with decreased lipid accumulation and cholesterol synthesis in a hepatic zone 1-specifi c manner by increasing expression of carnitine palmitotyltransferase1 and phosphorylation of 3-hydroxy-3-methyl-glutaryl-CoA reductase via an AR-mediated pathway. E2+DHT showed an additive positive effect and normalized all three impaired zones of the liver. Gene expression changes in human severe liver steatosis were similar to those of experimental rat NAFLD. Steroids reversed the histopathological NAFLD changes, likely by decreasing fatty acid and cholesterol synthesis and increasing ␤ -oxidation. The diverse steroid effects (ER/AR) on NAFLD prevention in male rats indicate the potential applicability of ER/AR modulators for NAFLD treatment. -

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Dihydrotestosterone Treatment Results in Obesity and Altered Lipid Metabolism in Orchidectomized Mice

Cited by 95 publications

References 60 publications

Testosterone: a metabolic hormone in health and disease

Testosterone: a metabolic hormone in health and disease

Neuropeptide Y and sex hormone interactions in humoral and neuronal regulation of bone and fat

Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat

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