Lori Zeltser - Academia.edu (original) (raw)

Papers by Lori Zeltser

Nature Reviews Neuroscience

Nature communications, May 29, 2018

Evidence of male-to-female sexual transmission of Zika virus (ZIKV) and viral RNA in semen and sp... more Evidence of male-to-female sexual transmission of Zika virus (ZIKV) and viral RNA in semen and sperm months after infection supports a potential role for testicular cells in ZIKV propagation. Here, we demonstrate that germ cells (GCs) are most susceptible to ZIKV. We found that only GCs infected by ZIKV, but not those infected by dengue virus and yellow fever virus, produce high levels of infectious virus. This observation coincides with decreased expression of interferon-stimulated gene Ifi44l in ZIKV-infected GCs, and overexpression of Ifi44l results in reduced ZIKV production. Using primary human testicular tissue, we demonstrate that human GCs are also permissive for ZIKV infection and production. Finally, we identified berberine chloride as a potent inhibitor of ZIKV infection in both murine and human testes. Together, these studies identify a potential cellular source for propagation of ZIKV in testes and a candidate drug for preventing sexual transmission of ZIKV.

Endocrine reviews, Aug 1, 2017

Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that i... more Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggest...

Nature, Mar 8, 2017

Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, F... more Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood-brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with meta...

PloS one, 2017

Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal ... more Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates l...

Molecular Metabolism, 2016

Objective: Humans and animals exposed to undernutrition (UN) during development often experience ... more Objective: Humans and animals exposed to undernutrition (UN) during development often experience accelerated "catch-up" growth when food supplies are plentiful. Little is known about the mechanisms regulating early growth rates. We previously reported that actions of leptin and presynaptic inputs to orexigenic NPY/AgRP/GABA (NAG) neurons in the arcuate nucleus of the hypothalamus are almost exclusively excitatory during the lactation period, since neuronal and humoral inhibitory systems do not develop until after weaning. Moreover, we identified a critical step that regulates the maturation of electrophysiological responses of NAG neurons at weaning e the onset of genes encoding ATP-dependent potassium (K ATP) channel subunits. We explored the possibility that UN promotes subsequent catch-up growth, in part, by delaying the maturation of negative feedback systems to neuronal circuits driving food intake. Methods: We used the large litter (LL) size model to study the impacts of postnatal UN followed by catch-up growth. We evaluated the maturation of presynaptic and postsynaptic inhibitory systems in NAG neurons using a combination of electrophysiological and molecular criteria, in conjunction with leptin's ability to suppress fasting-induced hyperphagia. Results: The onset of K ATP channel subunit expression and function, the switch in leptin's effect on NAG neurons, the ingrowth of inhibitory inputs to NAG neurons, and the development of homeostatic feedback to feeding circuits were delayed in LL offspring relative to controls. The development of functional K ATP channels and the establishment of leptin-mediated suppression of food intake in the peri-weaning period were tightly linked and were not initiated until growth and adiposity of LL offspring caught up to controls. Conclusions: Our data support the idea that initiation of K ATP channel subunit expression in NAG neurons serves as a molecular gatekeeper for the maturation of homeostatic feeding circuits.

Endocrinology, Jan 20, 2015

While most adults can lose weight by dieting, a well-characterized compensatory decrease in energ... more While most adults can lose weight by dieting, a well-characterized compensatory decrease in energy expenditure promotes weight regain more than 90 of the time. Using mice with impaired hypothalamic leptin signaling as a model of early-onset hyperphagia and obesity, we explored whether this unfavorable response to weight loss could be circumvented by early intervention. Early-onset obesity was associated with impairments in the structure and function of brown adipose tissue (BAT) mitochondria, which were ameliorated by weight loss at any age. Whereas decreased sympathetic tone in weight-reduced adults resulted in net reductions in BAT thermogenesis and energy expenditure that promoted rapid weight regain, this was not the case when dietary interventions were initiated at weaning. Enhanced energy expenditure persisted even after mice were allowed to resume over-eating, leading to lasting reductions in adiposity. These findings reveal a time window when dietary interventions can produc...

Frontiers in Neuroendocrinology, 2015

Suboptimal maternal nutrition exerts lasting impacts on obesity risk in offspring, but the direct... more Suboptimal maternal nutrition exerts lasting impacts on obesity risk in offspring, but the direction of the effect is determined by the timing of exposure. While maternal undernutrition in early pregnancy is associated with increased body mass index, in later pregnancy it can be protective. The importance of the timing of maternal undernutrition is also observed in rodents, however, many of the processes that occur in the last trimester of human gestation are delayed to the postnatal period. Neonatal leptin administration exerts lasting impacts on susceptibility to obesity in rodents. Although leptin can influence the formation of hypothalamic circuits involved in homeostatic control of feeding during the postnatal period, these effects are too late to account for its ability to reverse adverse metabolic programming due to early gestational exposure to maternal undernutrition. This review presents an alternative framework for understanding the effects of neonatal leptin through influences on developing thermoregulatory circuits.

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 23, 2014

Leptin is well known for its role in the regulation of energy homeostasis in adults, a mechanism ... more Leptin is well known for its role in the regulation of energy homeostasis in adults, a mechanism that at least partially results from the inhibition of the activity of NPY/AgRP/GABA neurons (NAG) in the arcuate nucleus of the hypothalamus (ARH). During early postnatal development in the rodent, leptin promotes axonal outgrowth from ARH neurons, and preautonomic NAG neurons are particularly responsive to leptin's trophic effects. To begin to understand how leptin could simultaneously promote axonal outgrowth from and inhibit the activity of NAG neurons, we characterized the electrochemical effects of leptin on NAG neurons in mice during early development. Here, we show that NAG neurons do indeed express a functional leptin receptor throughout the early postnatal period in the mouse; however, at postnatal days 13-15, leptin causes membrane depolarization in NAG neurons, rather than the expected hyperpolarization. Leptin action on NAG neurons transitions from stimulatory to inhibit...

Nucleic Acids Research, 2000

Initiation of DNA replication occurs with high frequency within oriβ β β β, a short region 3'... more Initiation of DNA replication occurs with high frequency within oriβ β β β, a short region 3' '' 'to the Chinese hamster dhfr gene. Homodimers of RIP60 (replication initiation-region protein 60 kDA) purified from nuclear extract bind two ATT-rich sites in oriβ β β β and foster the formation of a twisted 720 bp DNA loop in vitro. Using a

Nature Neuroscience, 2012

Maintaining energy balance is of paramount importance for metabolic health and survival. It is ac... more Maintaining energy balance is of paramount importance for metabolic health and survival. It is achieved through the coordinated regulation of neuronal circuits that control a wide range of physiological processes affecting energy intake and expenditure, such as feeding, metabolic rate, locomotor activity, arousal, growth and reproduction. Neuronal populations distributed throughout the CNS but highly enriched in the mediobasal hypothalamus, sense hormonal, nutrient and neuronal signals of systemic energy status and relay this information to secondary neurons that integrate the information and regulate distinct physiological parameters in a manner that promotes energy homeostasis. To achieve this, it is critical that neuronal circuits provide information about short-term changes in nutrient availability in the larger context of long-term energy status. For example, the same signals lead to different cellular and physiological responses if delivered under fasted versus fed conditions. Thus, there is a clear need to have mechanisms that rapidly and reversibly adjust responsiveness of hypothalamic circuits to acute changes in nutrient availability.

Proceedings of the National …, 2011