12-week Dolutegravir treatment marginally reduces energy expenditure but does not increase body weight or alter vascular function in a murine model of Human Immunodeficiency Virus infection.

Combination antiretroviral therapy (cART) has markedly increased life expectancy in people with HIV (PWH) but has also resulted in an increased prevalence of cardiometabolic disorders, whose etiopathology remains ill-defined. Notably, the respective contribution of cART and HIV-derived proteins to obesity and vascular alterations remain poorly understood. Therefore, we investigated the individual and combined effects of HIV-proteins and of the integrase strand transfer inhibitor Dolutegravir (DTG) on body composition and vascular reactivity. Male wildtype (WT) and HIV transgenic (Tg26) mice, received DTG or vehicle for 12 weeks. Viral proteins expression in Tg26 mice lowered fat mass, increased heat production, and induced a 2-fold increase in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) expression. DTG increased the expression of markers of adipogenesis in adipocytes in culture, but also reduced heat production and BAT UCP1 and UCP3 expression in Tg26 mice. DTG increased food intake, fat percentage and protected from lean mass reduction in Tg26 mice only. However, DTG did not increase body weight in either WT or Tg26 mice. Viral protein expression reduced acetylcholine (endothelium)-mediated relaxation by 14% in mesenteric arteries preconstricted with phenylephrine. However, DTG did not impair nor improve endothelium-dependent relaxation. Together, these data indicate that DTG's effects on food intake, adipogenesis and energy expenditure are insufficient to increase body weight, even in the presence of HIV-proteins, suggesting that body weight gain in PWH involves additional factors likely including other cART components and pre-existing comorbidities. Moreover, these data rule out DTG as a source of vascular disorders in PWH.

Neurons of the rat preoptic area and the raphe pallidus nucleus innervating the brown adipose tissue express the prostaglandin E receptor subtype EP3.

The major effector organ for thermogenesis during inflammation or experimental pyrogen-induced fever in rodents is the brown adipose tissue (BAT). Prostaglandin E2 (PGE2) microinjection into the medial preoptic area (POA) of rats leads to hyperthermia through an increase in BAT thermogenesis and induces pyrogenic signal transmission towards the raphe pallidus nucleus (RPa), a brainstem nucleus known to contain sympathetic premotor neurons for BAT control. The medial POA has a high expression of prostaglandin E receptor subtype EP3 (EP3R) on POA neurons, suggesting that these EP3R are main central targets of PGE2 to mediate BAT thermogenesis. To reveal central command neurons that contain EP3R and polysynaptically project to the BAT, we combined EP3R immunohistochemistry with the detection of transneuronally labelled neurons that were infected after injection of pseudorabies virus into the BAT. Neurons double-labelled with EP3R and viral surface antigens were particularly numerous in two brain regions, the medial POA and the RPa. Of all medial POA neurons that became virally infected 71 h after BAT inoculation, about 40% expressed the EP3R. This subpopulation of POA neurons is the origin of a complete neuronal chain that connects potential PGE2-sensitive POA neurons with the BAT. As for the efferent pathway of pyrogenic signal transmission, we hypothesize that neurons of this subpopulation of EP3R expressing POA neurons convey their pyrogenic signals towards the BAT via the RPa. We additionally observed that two-thirds of those RPa neurons that polysynaptically project to the interscapular BAT also expressed the EP3R, suggesting that RPa neurons themselves might possess prostaglandin sensitivity that is able to modulate BAT thermogenesis under febrile conditions.

Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure.

The thermogenic activity of interscapular brown adipose tissue (IBAT) in response to physiologic stimuli, such as cold exposure, is controlled by its sympathetic innervation. To determine which brain regions might be involved in the regulation of cold-evoked increases in sympathetic outflow to IBAT, the present study compared central nervous system (CNS) areas activated by cold exposure with brain regions anatomically linked to the sympathetic innervation of IBAT. Immunocytochemical localization of Fos was examined in the brains of rats exposed to 4 degrees C for 4 hours. In a separate group of rats, the neural circuit involved in IBAT control, including the location of sympathetic preganglionic neurons in the spinal cord, was characterized with pseudorabies virus, a retrograde transynaptic tracer. Central noradrenergic and serotonergic groups related to the sympathetic outflow to IBAT also were identified. Localization of viral antigens at different survival times (66-96 hours) revealed infection in circumscribed CNS populations, but only a subset of the regions comprising this circuitry showed cold-evoked Fos expression. The raphe pallidus and the ventromedial parvicellular subdivision of the paraventricular hypothalamic nucleus (PVH), both infected at early survival times, were the main areas containing sympathetic premotor neurons activated by cold exposure. Major cold-sensitive areas projecting to spinal interneurons or to regions containing sympathetic premotor neurons, which became infected at intermediate intervals, included lateral hypothalamic, perifornical, and retrochiasmatic areas, anterior and posterior PVH, ventrolateral periaqueductal gray, and Barrington's nucleus. Areas infected later, most likely related to reception of cold-related signals, comprised the lateral preoptic area, parastrial nucleus, dorsomedial hypothalamic nucleus, lateral parabrachial nucleus, and nucleus of the solitary tract. These interconnected areas, identified by combining functional and retrograde anatomic approaches, likely constitute the central circuitry responsible for the increase in sympathetic outflow to IBAT during cold-evoked thermogenesis.