Biology subjects

Nogueiras, R.

Publications and source records attributed to Nogueiras, R..

3 recordsLinked to original sources

bioRxiv2021

Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency

The solute carrier monocarboxylate transporter 8 (MCT8) transports the thyroid hormones thyroxine and tri-iodothyronine (T3) across cell membranes. MCT8 gene deficiency, termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. As no treatment of the neurological symptoms is available yet, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased T3 levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

neuroscience↗

bioRxiv2021

CaMK1D signaling in AgRP neurons promotes ghrelin-mediated food intake

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behavior. Ghrelin, a major hormone released under fasting conditions, activates orexigenic AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signaling mechanisms in AgRP/NPY neurons remain poorly defined. Here we demonstrate that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated in hypothalamus upon ghrelin stimulation and acts in AgRP neurons to promote ghrelin-dependent food intake. Global CaMK1D knockout mice are resistant to the orexigenic action of ghrelin, gain less body weight and are protected against high-fat diet-induced obesity. Deletion of CaMK1D in AgRP but not in POMC neurons is sufficient to recapitulate above phenotypes. Lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY as well as the amount of AgRP fiber projections to the Paraventricular nucleus (PVN), while electrical activity of AgRP neurons and 5 AMP-activated protein kinase (AMPK) signaling are unaffected. Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons. HighlightsO_LIWhole-body deletion of CaMK1D in mice reduces food intake, ghrelin sensitivity and protects against obesity. C_LIO_LIAgRP/NPY neuron-specific deletion of CaMK1D reduces food intake, ghrelin sensitivity, energy expenditure and protects against obesity. C_LIO_LICaMK1D is dispensable for ghrelin-stimulated electrical activity of AgRP neurons and hypothalamic AMPK signaling. C_LIO_LICaMK1D controls phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP and NPY. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/471546v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@40d7d7org.highwire.dtl.DTLVardef@11a8c64org.highwire.dtl.DTLVardef@1f6fad3org.highwire.dtl.DTLVardef@1cd5581_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Intestinal Gluconeogenesis Regulates Brown and White Adipose Tissues Functions in mice

ObjectiveIntestinal gluconeogenesis, via the initiation of a gut-brain nervous circuit, accounts for the metabolic benefits linked to dietary proteins or fermentable fibre in rodents and has been positively correlated with the rapid amelioration of body weight after gastric bypass surgery in obese humans. In particular, the activation of intestinal gluconeogenesis moderates the development of hepatic steatosis accompanying obesity. In this study, we investigated the specific effects of intestinal gluconeogenesis on adipose tissue metabolism, independently of its induction by nutritional manipulation. MethodsWe used two transgenic mouse models of suppression or overexpression of G6PC, the catalytic subunit of glucose-6 phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine. ResultsUnder a hypercaloric diet, mice with a genetic overexpression of intestinal gluconeogenesis showed a lower adiposity and higher thermogenic capacities than wild-type mice, featuring marked browning of white adipose tissue and prevention of the whitening of brown adipose tissue. Suppression of sympathetic nervous signalling in brown adipose tissue impairs the activation of thermogenesis. Conversely, mice with genetic suppression of intestinal gluconeogenesis exhibit an increase in adiposity under standard diet, associated with a decreased expression of markers of thermogenesis in both the brown and white adipose tissues. ConclusionIntestinal gluconeogenesis is sufficient in itself to activate the sympathetic nervous system and prevent the expansion and the metabolic alterations of brown and white adipose tissues metabolism under high calorie diet, thus preventing the development of obesity. These data increase knowledge of the mechanisms of weight reduction in gastric bypass surgery and pave the way of new approaches to prevent or cure obesity.

physiology↗