Human tactile sensibility in hairy skin is mediated not only by fast conducting myelinated (Aβ) afferents, but also by a system of slow conducting, unmyelinated afferents that respond preferentially to light touch, C-tactile (CT) afferents. This system has previously been shown to correlate with the pleasantness of tactile stimuli, where a soft brush moving at 1-3cm/s activates CT afferents strongly. Functional magnetic resonance imaging (fMRI) studies have shown that preferential CT fiber stimulation activates the posterior insula cortex. The present study aims to assess brain activity evoked by the activation of CT afferents using electroencephalography (EEG). We present evidence for a late cortical potential over frontal electrodes, evoked from slow, gentle brush strokes at 3cm/s. We relate this to the CT afferent input based on the conduction velocity of the CT fibers and the force feedback from the brush; the potential started 0.7s after the brush contacted the skin and continued throughout the brush stimulation. Furthermore, results from brushing at lower and higher speeds showed that the CT potential was modulated by this stimulation. We conclude that the late potential is consistent with activity in a frontal cortical network following hairy skin peripheral stimulation. This provides an important tool for further studies of the CT fiber system and for clinical examination of peripheral unmyelinated afferents.

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Intimal hyperplasia is a vascular pathological process involved in the pathogenesis of atherosclerosis. Data suggest that T, the most important sex steroid hormone in males, protects men from atherosclerotic cardiovascular disease. T mainly acts via the androgen receptor (AR), and in this study we evaluated formation of intimal hyperplasia in male AR knockout (ARKO) mice using a vascular injury model. Two weeks after ligation of the carotid artery, male ARKO mice showed increased intimal area and intimal thickness compared with controls. After endothelial denudation by an in vivo scraping injury, there was no difference in the reendothelialization in ARKO compared with control mice. Ex vivo, we observed increased outgrowth of vascular smooth muscle cells from ARKO compared with control aortic tissue explants; the number of outgrown cells was almost doubled in ARKO. In vitro, stimulation of human aortic vascular smooth muscle cells with a physiological T concentration inhibited both migration and proliferation of the cells. Analyzing the expression of central regulators of cell proliferation and migration, we found that mRNA and protein levels of p27 were lower in uninjured arteries from ARKO mice and that T replacement to castrated male mice increased p27 mRNA in an AR-dependent manner. In conclusion, AR deficiency in male mice increases intimal hyperplasia in response to vascular injury, potentially related to the effects of androgens/AR to inhibit proliferation and migration of smooth muscle cells.

Androgen deprivation therapy of prostate cancer, which suppresses serum testosterone to castrate levels, is associated with increased risk of heart failure. Here we tested the hypothesis that castration alters cardiac energy substrate uptake, which is tightly coupled to the regulation of cardiac structure and function. Short-term (3-4 weeks) surgical castration of male mice reduced the relative heart weight. While castration did not affect cardiac function in unstressed conditions, we observed reductions in heart rate, stroke volume, cardiac output and cardiac index during pharmacological stress with dobutamine in castrated versus sham-operated mice. Experiments using radiolabeled lipoproteins and glucose showed that castration shifted energy substrate uptake in the heart from lipids towards glucose, while testosterone replacement had the opposite effect. There was increased expression of fetal genes in the heart of castrated mice, including a strong increase in mRNA and protein levels of β-myosin heavy chain (MHC), the fetal isoform of MHC. In conclusion, castration of male mice induces metabolic remodeling and expression of the fetal gene program in the heart, in association with a reduced cardiac performance during pharmacological stress. These findings may be relevant for the selection of treatment strategies for heart failure in the setting of testosterone deficiency.

Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs. sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.

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