Clinical studies have indicated a link between Parkinson's disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function.

The antioxidant alpha-lipoic acid (LA) has been shown to improve insulin action in high-fat (HF)-fed animal models, yet little is known about its underlying mechanisms of action. We hypothesize that LA acts by inducing heat shock proteins (HSPs), which then inhibit stress kinases known to interfere with insulin signaling intermediates. Male Wistar rats were fed a HF diet (60% calories from fat) for 6 wk, while controls received a chow diet (10% calories from fat). One-half of the rats in each group received daily LA injections (30 mg/kg body wt). In rats fed a HF diet, LA increased expression of HSP72 and activation of HSP25 in soleus muscle, but it had no effect on HSPs in muscle from chow-fed rats. LA treatment reduced phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and inhibitor of kappaB kinase-beta (IKKbeta) activity (IkappaBalpha protein levels) in rats fed a HF diet and effectively restored insulin responsiveness, as seen by insulin-stimulated phosphorylated Akt/Akt and 2-deoxyglucose uptake in soleus muscle. LA also induced activation of p38 MAPK and AMP-activated protein kinase, proteins previously implicated in insulin-independent glucose uptake. In addition, acute LA treatment induced HSPs in vitro in L6 muscle cells and prevented the activation of JNK and IKKbeta with stimulants such as anisomycin and TNF-alpha, respectively. In conclusion, our results suggest chronic LA treatment results in stress kinase inhibition and improved insulin signaling through a HSP-mediated mechanism.

Non-technical summary Previous studies show that oestrogen is beneficial for maintaining blood glucose levels and helping the body respond to insulin. Despite these previous findings, the mechanism by which oestrogen acts is unknown. We show that specific activation of oestrogen receptor α (ERα) increases glucose uptake into skeletal muscle when insulin is present. Activation of oestrogen receptor β (ERβ) alone or activation of both ERα and ERβ together did not increase glucose uptake into skeletal muscle. This suggests that oestrogen's beneficial effect occurs by activating ERα. These results have important implications for understanding the mechanisms of glucose homeostasis, particularly in postmenopausal women with low oestrogen levels.Abstract Previous studies suggest oestrogen receptor α (ERα) is involved in oestrogen-mediated regulation of glucose metabolism and is critical for maintenance of whole body insulin action. Despite this, the effect of direct ERα modulation in insulin-responsive tissues is unknown. The purpose of the current study was to determine the impact of ERα activation, using the ER subtype-selective ligand propylpyrazoletriyl (PPT), on skeletal muscle glucose uptake. Two-month-old female Sprague-Dawley rats, ovariectomized for 1 week, were given subcutaneous injections of PPT (10 mg kg −1 ), oestradiol benzoate (EB; 20 μg kg −1 ), the ERβ agonist diarylpropionitrile (DPN, 10 mg kg −1 ) or vehicle every 24 h for 3 days. On the fourth day, insulin-stimulated skeletal muscle glucose uptake was measured in vitro and insulin signalling intermediates were assessed via Western blotting. Activation of ERα with PPT resulted in increased insulin-stimulated glucose uptake into the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles, activation of insulin signalling intermediates (as measured by phospho-Akt (pAkt) and pAkt substrate (PAS)) and phosphorylation of AMP-activated protein kinase (AMPK). GLUT4 protein was increased only in the EDL muscle. Rats treated with EB or DPN for 3 days did not show an increase in insulin-stimulated skeletal muscle glucose uptake compared to vehicle-treated animals. These new findings reveal that direct activation of ERα positively mediates glucose uptake and insulin action in skeletal muscle. Evidence that oestrogens and ERα stimulate glucose uptake has important implications for understanding mechanisms of glucose homeostasis, particularly in postmenopausal women.

Estrogen receptors (ERs) are expressed in adipose tissue and skeletal muscle, with potential implications for glucose metabolism and insulin signaling. Previous studies examining the role of ERs in glucose metabolism have primarily used knockout mouse models of ERα and ERβ, and it is unknown whether ER expression is altered in response to an obesity-inducing high-fat diet (HFD). The purpose of the current study was to determine whether modulation of glucose metabolism in response to a HFD in intact and ovariectomized (OVX) female rats is associated with alterations in ER expression. Our results demonstrate that a 6-wk HFD (60% calories from fat) in female rats induces whole body glucose intolerance with tissue-specific effects isolated to the adipose tissue, and no observed differences in insulin-stimulated glucose uptake, GLUT4, or ERα protein expression levels in skeletal muscle. In chow-fed rats, OVX resulted in decreased ERα with a trend toward decreased GLUT4 expression in adipose tissue. Sham-treated and OVX rats fed a HFD demonstrated a decrease in ERα and GLUT4 in adipose tissue. The HFD also increased activation of stress kinases (c-jun NH₂-terminal kinase and inhibitor of κB kinase β) in the sham-treated rats and decreased expression of the protective heat shock protein 72 (HSP72) in both sham-treated and OVX rats. Our findings suggest that decreased glucose metabolism and increased inflammation in adipose tissue with a HFD in female rats could stem from a significant decrease in ERα expression.

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