The Islet Estrogen Receptor-α Is Induced by Hyperglycemia and Protects Against Oxidative Stress-Induced Insulin-Deficient Diabetes

The female steroid, 17β-estradiol (E2), is important for pancreatic β-cell function and acts via at least three estrogen receptors (ER), ERα, ERβ, and the G-protein coupled ER (GPER). Using a pancreas-specific ERα knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERαKO−/−), we previously reported that islet ERα suppresses islet glucolipotoxicity and prevents β-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERα to prevent β-cell apoptosis in vivo. However, the contribution of the islet ERα to β-cell survival in vivo, without the contribution of ERα in other tissues is still unclear. Using the PERαKO−/− mouse, we show that ERα mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERα elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERαKO−/− mice exhibited a predisposition to β-cell destruction and insulin deficient diabetes. In male PERαKO−/− mice, exposure to E2 partially prevented alloxan-induced β-cell destruction and diabetes. ERα mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERα mRNA by hyperglycemia was retained in insulin receptor-deficient β-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERα expression acts to naturally protect β-cells against oxidative injury

The islet estrogen receptor-alpha is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes

The female steroid, 17beta-estradiol (E2), is important for pancreatic beta-cell function and acts via at least three estrogen receptors (ER), ERalpha, ERbeta, and the G-protein coupled ER (GPER). Using a pancreas-specific ERalpha knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERalphaKO (-)/(-)), we previously reported that islet ERalpha suppresses islet glucolipotoxicity and prevents beta-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERalpha to prevent beta-cell apoptosis in vivo. However, the contribution of the islet ERalpha to beta-cell survival in vivo, without the contribution of ERalpha in other tissues is still unclear. Using the PERalphaKO (-)/(-) mouse, we show that ERalpha mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERalpha elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERalphaKO (-)/(-) mice exhibited a predisposition to beta-cell destruction and insulin deficient diabetes. In male PERalphaKO (-)/(-) mice, exposure to E2 partially prevented alloxan-induced beta-cell destruction and diabetes. ERalpha mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERalpha mRNA by hyperglycemia was retained in insulin receptor-deficient beta-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERalpha expression acts to naturally protect beta-cells against oxidative injury

Direct and Indirect Innervation and Modulation of the Mesolimbic Dopamine System by Leptin Responsive Neurons.

Obesity is a burgeoning problem and a major risk factor for the development of Type-2 diabetes, cardiovascular disease, and cancer. This is likely caused by coupling of environments promoting an obesogenic lifestyle with biological systems that evolved to maintain body weight by responding to rewarding properties of food. It is crucial to understand systems that link energy balance and reward as we seek to define mechanisms that drive overeating and obesity. A major breakthrough in our understanding of energy homeostasis came with the discovery of the adipose-derived satiety factor, leptin. Leptin’s primary action in the brain is in the mediobasal hypothalamus where much of its anorectic effects are mediated. Recent research has shown that hypothalamic leptin signaling is inadequate to account for all of leptin’s actions in the brain. There are several leptin receptor-expressing neural populations that are may mediate reward sensation as they interact with elements of the mesolimbic dopamine system. Our goals were to interrogate leptin-responsive neural populations that interact with the mesolimbic dopamine reward system (MLDA) in an attempt to better understand the relationship between energy status and reward. We used novel leptin receptor (LepRb) specific tract tracing system to identify the circumscribed projection pattern of ventral tegmental area (VTA) LepRb neurons and their downstream targets. Additionally we investigated LepRb neurons in the lateral hypothalamic area (LHA) which are known to project locally to orexin neurons and indirectly to VTA dopamine (DA) neurons. Using molecular mouse models with deficient LepRb expression in LHA neurons we assessed how leptin acts through the LHA to modulate reward sensitivity. We also studied the role of the neuropeptide neurotensin in mediating LHA LepRb neural. We found that VTA LepRb neurons project to and regulate GABAergic CART neurons in the central amygdala where they presumably regulate limbic function while LHA LepRb neurons modulate striatal behaviors. These findings confirm the supposition that individual LepRb neural populations regulate distinct aspects of central leptin signaling as a whole. Advancing our knowledge of how systems that maintain energy balance interact with reward processing brain regions is an important step to our combating the development of obesity.Ph.D.NeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/84468/1/dopland_1.pd

Critical roles for the TSC-mTOR pathway in β-cell function

TSC1 is a tumor suppressor that associates with TSC2 to inactivate Rheb, thereby inhibiting signaling by the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 stimulates cell growth by promoting anabolic cellular processes, such as translation, in response to growth factors and nutrient signals. To test roles for TSC1 and mTORC1 in β-cell function, we utilized Rip2/Cre to generate mice lacking Tsc1 in pancreatic β-cells (Rip-Tsc1cKO mice). Although obesity developed due to hypothalamic Tsc1 excision in older Rip-Tsc1cKO animals, young animals displayed a prominent gain-of-function β-cell phenotype prior to the onset of obesity. The young Rip-Tsc1cKO animals displayed improved glycemic control due to mTOR-mediated enhancement of β-cell size, mass, and insulin production but not determinants of β-cell number (proliferation and apoptosis), consistent with an important anabolic role for mTOR in β-cell function. Furthermore, mTOR mediated these effects in the face of impaired Akt signaling in β-cells. Thus, mTOR promulgates a dominant signal to promote β-cell/islet size and insulin production, and this pathway is crucial for β-cell function and glycemic control

Neuropeptide y activity in the nucleus accumbens modulates feeding behavior and neuronal activity. Biological Psychiatry. http:// dx.doi.org/10.1016/j.biopsych.2014.06.008. under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0

Abstract Background-Neuropeptide Y (NPY) is a hypothalamic neuropeptide that plays a prominent role in feeding and energy homeostasis. Expression of the NPY Y1 receptor (Y1R) is highly concentrated in the nucleus accumbens (Acb), a region important in the regulation of palatable feeding. In this study, we performed a number of experiments to investigate the actions of NPY in the Acb

Striatal dopamine regulates systemic glucose metabolism in humans and mice

The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. We present a series of experiments supporting the regulation of peripheral glucose metabolism by striatal dopamine signaling. First, we present the case of a diabetes patient who displayed strongly reduced insulin requirements after treatment with bilateral deep brain stimulation (DBS) targeting the anterior limb of the internal capsule. Next, we show that DBS in this striatal area, which induced dopamine release, increased hepatic and peripheral insulin sensitivity in 14 nondiabetic patients with obsessive-compulsive disorder. Conversely, systemic dopamine depletion reduced peripheral insulin sensitivity in healthy subjects. Supporting these human data, we demonstrate that optogenetic activation of dopamine D1 receptor–expressing neurons in the nucleus accumbens increased glucose tolerance and insulin sensitivity in mice. Together, these findings support the hypothesis that striatal neuronal activity regulates systemic glucose metabolism

ERα expression in PERαKO^−/− hypothalamus.

<p>Pdx1-Cre/Lacz mouse and immunofluorescence in frontal brain sections from PERαKO^−/− mice. Pdx-1 expression (red) marked by beta galactosidase (β-gal) and ERα (green) show PDX-1 and ERα co-expression in the ventromedial hypothalamus (VMH), the preoptic area and arcuate nucleus (ARC) <b>(A–B)</b>. and quantification <b>(C)</b> Bar represents 250 µm. Representative images of immunohistochemical analisys showing ERα expression in frontal brain sections from ERα fl/fl, <b>(D)</b> ERαKO^−/−<b>(E)</b> and PERαKO^−/−<b>(F)</b> mice Pictures taken at 10X magnification and quantification <b>(G)</b>.</p

Male PERαKO^−/− mice are susceptible to ALX-induced diabetes.

<p><b>(A)</b> Random-fed blood glucose from day 0 to day 11 after injection of either 150 mg/Kg of ALX or saline. <b>(B)</b> Corresponding area under the curve (AUC) for glucose. <b>(C)</b> Ratio of random-fed of insulin (ng/ml) and glucose (mg/dl) at day 11 was used as an index of insulin deficiency. <b>(D)</b> Representative sections showing immunofluorescent histochemical analysis of pancreas sections stained for insulin (green) and glucagon (red) in control ERαlox^+/+ and PERαKO^−/− mice <b>(E)</b> β-cell mass quantification <b>(F)</b> Pancreas insulin concentration 11 day after ALX injection. Values represent the mean±SEM, n = 4–19/group. *P<0.05, ***P<0.001, #  = 0.06. Bar represents 100 µm.</p