Publications by authors named "David P Olson"

59 Publications

Paraventricular Calcitonin Receptor Expressing Neurons Modulate Energy Homeostasis in Male Mice.

Endocrinology 2021 Apr 9. Epub 2021 Apr 9.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.

The paraventricular nucleus of the hypothalamus (PVH) is a heterogeneous collection of neurons that play important roles in modulating feeding and energy expenditure. Abnormal development or ablation of the PVH results in hyperphagic obesity and defects in energy expenditure whereas selective activation of defined PVH neuronal populations can suppress feeding and may promote energy expenditure. Here, we characterize the contribution of calcitonin receptor-expressing PVH neurons (CalcR PVH) to energy balance control. We used Cre-dependent viral tools delivered stereotaxically to the PVH of CalcR 2Acre mice to activate, silence and trace CalcR PVH neurons and determine their contribution to body weight regulation. Immunohistochemistry of fluorescently-labelled CalcR PVH neurons demonstrates that CalcR PVH neurons are largely distinct from several PVH neuronal populations involved in energy homeostasis; these neurons project to regions of the hindbrain that are implicated in energy balance control, including the nucleus of the solitary tract and the parabrachial nucleus. Acute activation of CalcR PVH neurons suppresses feeding without appreciably augmenting energy expenditure, whereas their silencing leads to obesity that may be due in part due to loss of PVH melanocortin-4 receptor (MC4R) signaling. These data show that CalcR PVH neurons are an essential component of energy balance neurocircuitry and their function is important for body weight maintenance. A thorough understanding of the mechanisms by which CalcR PVH neurons modulate energy balance might identify novel therapeutic targets for the treatment and prevention of obesity.
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http://dx.doi.org/10.1210/endocr/bqab072DOI Listing
April 2021

Melanocortin 3 receptor-expressing neurons in the ventromedial hypothalamus promote glucose disposal.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;

The ventromedial hypothalamus (VMH) is a critical neural node that senses blood glucose and promotes glucose utilization or mobilization during hypoglycemia. The VMH neurons that control these distinct physiologic processes are largely unknown. Here, we show that melanocortin 3 receptor ()-expressing VMH neurons (VMH) sense glucose changes both directly and indirectly via altered excitatory input. We identify presynaptic nodes that potentially regulate VMH neuronal activity, including inputs from proopiomelanocortin (POMC)-producing neurons in the arcuate nucleus. We find that VMH neuron activation blunts, and their silencing enhances glucose excursion following a glucose load. Overall, these findings demonstrate that VMH neurons are a glucose-responsive hypothalamic subpopulation that promotes glucose disposal upon activation; this highlights a potential site for targeting dysregulated glycemia.
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http://dx.doi.org/10.1073/pnas.2103090118DOI Listing
April 2021

tTARGIT AAVs mediate the sensitive and flexible manipulation of intersectional neuronal populations in mice.

Elife 2021 Mar 11;10. Epub 2021 Mar 11.

Department of Internal Medicine, University of Michigan, Ann Arbor, United States.

While Cre-dependent viral systems permit the manipulation of many neuron types, some cell populations cannot be targeted by a single DNA recombinase. Although the combined use of Flp and Cre recombinases can overcome this limitation, insufficient recombinase activity can reduce the efficacy of existing Cre+Flp-dependent viral systems. We developed a sensitive dual recombinase-activated viral approach: tTA-driven Recombinase-Guided Intersectional Targeting (tTARGIT) adeno-associated viruses (AAVs). tTARGIT AAVs utilize a Flp-dependent tetracycline transactivator (tTA) 'Driver' AAV and a tetracycline response element-driven, Cre-dependent 'Payload' AAV to express the transgene of interest. We employed this system in mice to manipulate LepRb neurons of the ventromedial hypothalamus (VMH; LepRb neurons) while omitting neighboring LepRb populations. We defined the circuitry of LepRb neurons and roles for these cells in the control of food intake and energy expenditure. Thus, the tTARGIT system mediates robust recombinase-sensitive transgene expression, permitting the precise manipulation of previously intractable neural populations.
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http://dx.doi.org/10.7554/eLife.66835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026215PMC
March 2021

GFRAL-expressing neurons suppress food intake via aversive pathways.

Proc Natl Acad Sci U S A 2021 Feb;118(8)

Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated and conditional mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRP) neurons. Silencing CGRP neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.
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http://dx.doi.org/10.1073/pnas.2021357118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923658PMC
February 2021

Decreased sensitivity to the anorectic effects of leptin in mice that lack a Pomc-specific neural enhancer.

PLoS One 2020 31;15(12):e0244793. Epub 2020 Dec 31.

Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

Enhancer redundancy has been postulated to provide a buffer for gene expression against genetic and environmental perturbations. While work in Drosophila has identified functionally overlapping enhancers, work in mammalian models has been limited. Recently, we have identified two partially redundant enhancers, nPE1 and nPE2, that drive proopiomelanocortin gene expression in the hypothalamus. Here we demonstrate that deletion of nPE1 produces mild obesity while knockout of nPE2 has no discernible metabolic phenotypes. Additionally, we show that acute leptin administration has significant effects on nPE1 knockout mice, with food intake and body weight change significantly impacted by peripheral leptin treatment. nPE1 knockout mice became less responsive to leptin treatment over time as percent body weight change increased over 2 week exposure to peripheral leptin. Both Pomc and Agrp mRNA were not differentially affected by chronic leptin treatment however we did see a decrease in Pomc and Agrp mRNA in both nPE1 and nPE2 knockout calorie restricted mice as compared to calorie restricted PBS-treated WT mice. Collectively, these data suggest dynamic regulation of Pomc by nPE1 such that mice with nPE1 knockout become less responsive to the anorectic effects of leptin treatment over time. Our results also support our earlier findings in which nPE2 may only be critical in adult mice that lack nPE1, indicating that these neural enhancers work synergistically to influence metabolism.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244793PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775064PMC
March 2021

Prenatal Androgenization Alters the Development of GnRH Neuron and Preoptic Area RNA Transcripts in Female Mice.

Endocrinology 2020 11;161(11)

Department of Molecular and Integrative Physiology, Ann Arbor, Michigan.

Polycystic ovary syndrome (PCOS) is the most common form of infertility in women. The causes of PCOS are not yet understood and both genetics and early-life exposure have been considered as candidates. With regard to the latter, circulating androgens are elevated in mid-late gestation in women with PCOS, potentially exposing offspring to elevated androgens in utero; daughters of women with PCOS are at increased risk for developing this disorder. Consistent with these clinical observations, prenatal androgenization (PNA) of several species recapitulates many phenotypes observed in PCOS. There is increasing evidence that symptoms associated with PCOS, including elevated luteinizing hormone (LH) (and presumably gonadotropin-releasing hormone [GnRH]) pulse frequency emerge during the pubertal transition. We utilized translating ribosome affinity purification coupled with ribonucleic acid (RNA) sequencing to examine GnRH neuron messenger RNAs from prepubertal (3 weeks) and adult female control and PNA mice. Prominent in GnRH neurons were transcripts associated with protein synthesis and cellular energetics, in particular oxidative phosphorylation. The GnRH neuron transcript profile was affected more by the transition from prepuberty to adulthood than by PNA treatment; however, PNA did change the developmental trajectory of GnRH neurons. This included families of transcripts related to both protein synthesis and oxidative phosphorylation, which were more prevalent in adults than in prepubertal mice but were blunted in PNA adults. These findings suggest that prenatal androgen exposure can program alterations in the translatome of GnRH neurons, providing a mechanism independent of changes in the genetic code for altered expression.
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http://dx.doi.org/10.1210/endocr/bqaa166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583650PMC
November 2020

Hypothalamic and Cell-Specific Transcriptomes Unravel a Dynamic Neuropil Remodeling in Leptin-Induced and Typical Pubertal Transition in Female Mice.

iScience 2020 Oct 16;23(10):101563. Epub 2020 Sep 16.

Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.

Epidemiological and genome-wide association studies (GWAS) have shown high correlation between childhood obesity and advance in puberty. Early age at menarche is associated with a series of morbidities, including breast cancer, cardiovascular diseases, type 2 diabetes, and obesity. The adipocyte hormone leptin signals the amount of fat stores to the neuroendocrine reproductive axis via direct actions in the brain. Using mouse genetics, we and others have identified the hypothalamic ventral premammillary nucleus (PMv) and the agouti-related protein (AgRP) neurons in the arcuate nucleus (Arc) as primary targets of leptin action in pubertal maturation. However, the molecular mechanisms underlying leptin's effects remain unknown. Here we assessed changes in the PMv and Arc transcriptional program during leptin-stimulated and typical pubertal development using overlapping analysis of bulk RNA sequecing, TRAP sequencing, and the published database. Our findings demonstrate that dynamic somatodendritic remodeling and extracellular space organization underlie leptin-induced and typical pubertal maturation in female mice.
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http://dx.doi.org/10.1016/j.isci.2020.101563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522126PMC
October 2020

Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations.

Nat Commun 2020 09 2;11(1):4410. Epub 2020 Sep 2.

Department of Neurology, Beth Israel Deaconess Medical Center, Division of Sleep Medicine, Harvard Medical School, Boston, MA, 02215, USA.

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCN) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCN neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCN neurons may regulate LMA rhythms. In vivo photometry revealed that while SCN neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCN neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCN neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCN cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCN subtypes.
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http://dx.doi.org/10.1038/s41467-020-17197-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468160PMC
September 2020

Whole-brain efferent and afferent connectivity of mouse ventral tegmental area melanocortin-3 receptor neurons.

J Comp Neurol 2021 Apr 10;529(6):1157-1183. Epub 2020 Sep 10.

Department of Biology, Georgia State University, Atlanta, Georgia, USA.

The mesolimbic dopamine (DA) system is involved in the regulation of multiple behaviors, including feeding, and evidence demonstrates that the melanocortin system can act on the mesolimbic DA system to control feeding and other behaviors. The melanocortin-3 receptor (MC3R) is an important component of the melanocortin system, but its overall role is poorly understood. Because MC3Rs are highly expressed in the ventral tegmental area (VTA) and are likely to be the key interaction point between the melanocortin and mesolimbic DA systems, we set out to identify both the efferent projection patterns of VTA MC3R neurons and the location of the neurons providing afferent input to them. VTA MC3R neurons were broadly connected to neurons across the brain but were strongly connected to a discrete set of brain regions involved in the regulation of feeding, reward, and aversion. Surprisingly, experiments using monosynaptic rabies virus showed that proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons in the arcuate nucleus made few direct synapses onto VTA MC3R neurons or any of the other major neuronal subtypes in the VTA, despite being extensively labeled by general retrograde tracers injected into the VTA. These results greatly contribute to our understanding of the anatomical interactions between the melanocortin and mesolimbic systems and provide a foundation for future studies of VTA MC3R neurons and the circuits containing them in the control of feeding and other behaviors.
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http://dx.doi.org/10.1002/cne.25013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867604PMC
April 2021

Dual-Color Single-Cell Imaging of the Suprachiasmatic Nucleus Reveals a Circadian Role in Network Synchrony.

Neuron 2020 10 7;108(1):164-179.e7. Epub 2020 Aug 7.

Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA. Electronic address:

The suprachiasmatic nucleus (SCN) acts as a master pacemaker driving circadian behavior and physiology. Although the SCN is small, it is composed of many cell types, making it difficult to study the roles of particular cells. Here we develop bioluminescent circadian reporter mice that are Cre dependent, allowing the circadian properties of genetically defined populations of cells to be studied in real time. Using a Color-Switch PER2::LUCIFERASE reporter that switches from red PER2::LUCIFERASE to green PER2::LUCIFERASE upon Cre recombination, we assess circadian rhythms in two of the major classes of peptidergic neurons in the SCN: AVP (arginine vasopressin) and VIP (vasoactive intestinal polypeptide). Surprisingly, we find that circadian function in AVP neurons, not VIP neurons, is essential for autonomous network synchrony of the SCN and stability of circadian rhythmicity.
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http://dx.doi.org/10.1016/j.neuron.2020.07.012DOI Listing
October 2020

Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance.

Sci Rep 2020 03 26;10(1):5546. Epub 2020 Mar 26.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Understanding the neural components modulating feeding-related behavior and energy expenditure is crucial to combating obesity and its comorbidities. Neurons within the paraventricular nucleus of the hypothalamus (PVH) are a key component of the satiety response; activation of the PVH decreases feeding and increases energy expenditure, thereby promoting negative energy balance. In contrast, PVH ablation or silencing in both rodents and humans leads to substantial obesity. Recent studies have identified genetically-defined PVH subpopulations that control discrete aspects of energy balance (e.g. oxytocin (OXT), neuronal nitric oxide synthase 1 (NOS1), melanocortin 4-receptor (MC4R), prodynorphin (PDYN)). We previously demonstrated that non-OXT NOS1 neurons contribute to PVH-mediated feeding suppression. Here, we identify and characterize a non-OXT, non-NOS1 subpopulation of PVH and peri-PVH neurons expressing insulin-receptor substrate 4 (IRS4) involved in energy balance control. Using Cre-dependent viral tools to activate, trace and silence these neurons, we highlight the sufficiency and necessity of IRS4 neurons in normal feeding and energy expenditure regulation. Furthermore, we demonstrate that IRS4 neurons lie within a complex hypothalamic circuitry that engages distinct hindbrain regions and is innervated by discrete upstream hypothalamic sites. Overall, we reveal a requisite role for IRS4 neurons in PVH-mediated energy balance which raises the possibility of developing novel approaches targeting IRS4 neurons for anti-obesity therapies.
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http://dx.doi.org/10.1038/s41598-020-62468-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099088PMC
March 2020

Leptin receptor-expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice.

JCI Insight 2020 04 9;5(7). Epub 2020 Apr 9.

Department of Internal Medicine and.

Leptin receptor-expressing (LepRb-expressing) neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and that produce the food intake-suppressing PPG cleavage product glucagon-like peptide-1 [GLP1]) represent a subpopulation of mouse LepRbNTS cells. Using Leprcre, Ppgcre, and Ppgfl mouse lines, along with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we examined roles for Ppg in GLP1NTS and LepRbNTS cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppgfl early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1NTS cells decreased food intake, LepRbNTS cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppgfl blunted the ability of GLP1NTS neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRbNTS cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1NTS cells, additional pathways engaged by LepRbNTS cells dominate for the suppression of food intake.
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http://dx.doi.org/10.1172/jci.insight.134359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205255PMC
April 2020

Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin.

J Clin Invest 2020 06;130(6):2943-2952

Department of Internal Medicine and.

To identify neurons that specifically increase blood glucose from among the diversely functioning cell types in the ventromedial hypothalamic nucleus (VMN), we studied the cholecystokinin receptor B-expressing (CCKBR-expressing) VMN targets of glucose-elevating parabrachial nucleus neurons. Activation of these VMNCCKBR neurons increased blood glucose. Furthermore, although silencing the broader VMN decreased energy expenditure and promoted weight gain without altering blood glucose levels, silencing VMNCCKBR neurons decreased hIepatic glucose production, insulin-independently decreasing blood glucose without altering energy balance. Silencing VMNCCKBR neurons also impaired the counterregulatory response to insulin-induced hypoglycemia and glucoprivation and replicated hypoglycemia-associated autonomic failure. Hence, VMNCCKBR cells represent a specialized subset of VMN cells that function to elevate glucose. These cells not only mediate the allostatic response to hypoglycemia but also modulate the homeostatic setpoint for blood glucose in an insulin-independent manner, consistent with a role for the brain in the insulin-independent control of glucose homeostasis.
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http://dx.doi.org/10.1172/JCI134135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260001PMC
June 2020

Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-aversive Suppression of Feeding.

Cell Metab 2020 02 16;31(2):301-312.e5. Epub 2020 Jan 16.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48105, USA; Division of Endocrinology, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48105, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48105, USA. Electronic address:

To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating Calcr neurons decreased food intake and body weight but (unlike neighboring Cck cells) failed to promote aversion, revealing that Calcr neurons mediate a non-aversive suppression of food intake. While both Calcr and Cck neurons decreased feeding via projections to the PBN, Cck cells activated aversive CGRP cells while Calcr cells activated distinct non-CGRP PBN cells. Hence, Calcr cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing Calcr cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, Calcr neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems.
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http://dx.doi.org/10.1016/j.cmet.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104375PMC
February 2020

The acute effects of nicotine on corticostriatal responses to distinct phases of reward processing.

Neuropsychopharmacology 2020 06 13;45(7):1207-1214. Epub 2020 Jan 13.

McLean Imaging Center, McLean Hospital, Belmont, MA, USA.

Nicotine enhances the reinforcement of non-drug rewards by increasing nucleus accumbens (NAcc) reactivity to anticipatory cues. This anticipatory effect is selective as no clear evidence has emerged showing that nicotine acutely changes reward receipt reactivity. However, repeated rewarding experiences shift peak brain reactivity from hedonic reward outcome to the motivational anticipatory cue yielding more habitual cue-induced behavior. Given nicotine's influence on NAcc reactivity and connectivity, it is plausible that nicotine acutely induces this shift and alters NAcc functional connectivity during reward processing. To evaluate this currently untested hypothesis, a randomized crossover design was used in which healthy non-smokers were administered placebo and nicotine (2-mg lozenge). Brain activation to monetary reward anticipation and outcome was evaluated with functional magnetic resonance imaging. Relative to placebo, nicotine induced more NAcc reactivity to reward anticipation. Greater NAcc activation during anticipation was significantly associated with lower NAcc activation to outcome. During outcome, nicotine reduced NAcc functional connectivity with cortical regions including the anterior cingulate cortex, orbitofrontal cortex, and insula. These regions showed the same negative relationship between reward anticipation and outcome as noted in the NAcc. The current findings significantly improve our understanding of how nicotine changes corticostriatal circuit function and communication during distinct phases of reward processing and critically show that these alterations happen acutely following a single dose. The implications of this work explain nicotinic modulation of general reward function, which offer insights into the initial drive to smoke and the subsequent difficulty in cessation.
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http://dx.doi.org/10.1038/s41386-020-0611-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235267PMC
June 2020

Inflammation and depressive phenotypes: evidence from medical records from over 12 000 patients and brain morphology.

Psychol Med 2020 12 16;50(16):2790-2798. Epub 2019 Oct 16.

Department of Psychiatry, Harvard Medical School, Boston, MA02115, USA.

Background: Preclinical and human studies suggest an association between chronic inflammation and the development of depressive behaviors. This is proposed to occur through downstream effects of inflammatory cytokines on neuroplasticity, neurogenesis and neurotransmitter function, although the neural correlates remain poorly understood in humans.

Methods: In Study 1, structural magnetic resonance imaging and serum inflammatory cytokine data were analyzed from 53 psychiatrically healthy female participants. Correlational analyses were conducted between interleukin-6 (IL-6) and volume in a priori regions implicated in the pathophysiology of major depressive disorder (MDD). In Study 2, medical data [including serum inflammatory acute phase reactants (C-reactive protein)] were analyzed for 12 589 participants. Participants were classified as having (n = 2541) v. not having (n = 10 048) probable lifetime MDD using phenotypes derived using machine-learning approaches. Non-parametric analyses compared inflammation between groups, whereas regression analyses probed whether inflammation predicted probable MDD classification while accounting for other variables.

Results: In Study 1, significant negative correlations emerged between IL-6 and hippocampal, caudate, putamen and amygdalar volume. In Study 2, the MDD group showed a higher probability of elevated inflammation than the non-MDD group. Moreover, elevated inflammation was a significant predictor of probable MDD classification.

Conclusions: Findings indicate that inflammation is cross-sectionally related to reduced volume in brain regions implicated in MDD phenotypes among a sample of psychiatrically healthy women, and is associated with the presence of probable MDD in a large clinical dataset. Future investigations may identify specific inflammatory markers predicting first MDD onset.
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http://dx.doi.org/10.1017/S0033291719002940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160032PMC
December 2020

Alpha-melanocyte stimulating hormone increases the activity of melanocortin-3 receptor-expressing neurons in the ventral tegmental area.

J Physiol 2019 06 26;597(12):3217-3232. Epub 2019 May 26.

Department of Biology.

Key Points: Alpha-melanocyte stimulating hormone (α-MSH) is an anorexigenic peptide. Injection of the α-MSH analog MTII into the ventral tegmental area (VTA) decreases food and sucrose intake and food reward. Melanocortin-3 receptors (MC3R) are highly expressed in the VTA, suggesting that the effects of intra-VTA α-MSH may be mediated by α-MSH changing the activity of MC3R-expressing VTA neurons. α-MSH increased the firing rate of MC3R VTA neurons in acute brain slices from mice, although it did not affect the firing rate of non-MC3R VTA neurons. The α-MSH induced increase in MC3R neuron firing rate is probably activity-dependent, and was independent of fast synaptic transmission and intracellular Ca levels. These results help us to better understand how α-MSH acts in the VTA to affect feeding and other dopamine-dependent behaviours.

Abstract: The mesocorticolimbic dopamine system, the brain's reward system, regulates multiple behaviours, including food intake and food reward. There is substantial evidence that the melanocortin system of the hypothalamus, an important neural circuit controlling feeding and body weight, interacts with the mesocorticolimbic dopamine system to affect feeding, food reward and body weight. For example, melanocortin-3 receptors (MC3Rs) are expressed in the ventral tegmental area (VTA) and our laboratory previously showed that intra-VTA injection of the MC3R agonist, MTII, decreases home-cage food intake and operant responding for sucrose pellets. However, the cellular mechanisms underlying the effects of intra-VTA alpha-melanocyte stimulating hormone (α-MSH) on feeding and food reward are unknown. To determine how α-MSH acts in the VTA to affect feeding, we performed electrophysiological recordings in acute brain slices from mice expressing enhanced yellow fluorescent protein in MC3R neurons to test how α-MSH affects the activity of VTA MC3R neurons. α-MSH significantly increased the firing rate of VTA MC3R neurons without altering the activity of non-MC3R expressing VTA neurons. In addition, the α-MSH-induced increase in MC3R neuron activity was independent of fast synaptic transmission and intracellular Ca levels. Finally, we show that the effect of α-MSH on MC3R neuron firing rate is probably activity-dependent. Overall, these studies provide an important advancement in the understanding of how α-MSH acts in the VTA to affect feeding and food reward.
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http://dx.doi.org/10.1113/JP277193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666402PMC
June 2019

Distinct Subsets of Lateral Hypothalamic Neurotensin Neurons are Activated by Leptin or Dehydration.

Sci Rep 2019 02 12;9(1):1873. Epub 2019 Feb 12.

Institute for Integrative Toxicology at Michigan State University, East Lansing, 48824, MI, USA.

The lateral hypothalamic area (LHA) is essential for ingestive behavior but it remains unclear how LHA neurons coordinate feeding vs. drinking. Most LHA populations promote food and water consumption but LHA neurotensin (Nts) neurons preferentially induce water intake while suppressing feeding. We identified two molecularly and projection-specified subpopulations of LHA Nts neurons that are positioned to coordinate either feeding or drinking. One subpopulation co-expresses the long form of the leptin receptor (LepRb) and is activated by the anorectic hormone leptin (Nts neurons). A separate subpopulation lacks LepRb and is activated by dehydration (Nts neurons). These molecularly distinct LHA Nts subpopulations also differ in connectivity: Nts neurons project to the ventral tegmental area and substantia nigra compacta but Nts neurons do not. Intriguingly, the LHA Nts subpopulations cannot be discriminated via their classical neurotransmitter content, as we found that all LHA Nts neurons are GABAergic. Collectively, our data identify two molecularly- and projection-specified subpopulations of LHA Nts neurons that intercept either leptin or dehydration cues, and which conceivably could regulate feeding vs. drinking behavior. Selective regulation of these LHA Nts subpopulations might be useful to specialize treatment for ingestive disorders such as polydipsia or obesity.
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http://dx.doi.org/10.1038/s41598-018-38143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372669PMC
February 2019

Respiratory Phenomics across Multiple Models of Protein Hyperacylation in Cardiac Mitochondria Reveals a Marginal Impact on Bioenergetics.

Cell Rep 2019 02;26(6):1557-1572.e8

Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, NC 27701, USA; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA; Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

Acyl CoA metabolites derived from the catabolism of carbon fuels can react with lysine residues of mitochondrial proteins, giving rise to a large family of post-translational modifications (PTMs). Mass spectrometry-based detection of thousands of acyl-PTMs scattered throughout the proteome has established a strong link between mitochondrial hyperacylation and cardiometabolic diseases; however, the functional consequences of these modifications remain uncertain. Here, we use a comprehensive respiratory diagnostics platform to evaluate three disparate models of mitochondrial hyperacylation in the mouse heart caused by genetic deletion of malonyl CoA decarboxylase (MCD), SIRT5 demalonylase and desuccinylase, or SIRT3 deacetylase. In each case, elevated acylation is accompanied by marginal respiratory phenotypes. Of the >60 mitochondrial energy fluxes evaluated, the only outcome consistently observed across models is a ∼15% decrease in ATP synthase activity. In sum, the findings suggest that the vast majority of mitochondrial acyl PTMs occur as stochastic events that minimally affect mitochondrial bioenergetics.
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http://dx.doi.org/10.1016/j.celrep.2019.01.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478502PMC
February 2019

Transcriptional and physiological roles for STAT proteins in leptin action.

Mol Metab 2019 04 24;22:121-131. Epub 2019 Jan 24.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Objectives: Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression.

Methods: Because STAT3 is crucial for physiologic leptin action, we used TRAP-seq to examine gene expression in LepRb neurons of mice ablated for Stat3 in LepRb neurons (Stat3KO mice), revealing the STAT3-dependent transcriptional targets of leptin. To understand roles for STAT proteins in leptin action, we also ablated STAT1 or STAT5 from LepRb neurons and expressed a constitutively-active STAT3 (CASTAT3) in LepRb neurons.

Results: While we also found increased Stat1 expression and STAT1-mediated transcription of leptin-regulated genes in Stat3KO mice, ablating Stat1 in LepRb neurons failed to alter energy balance (even on the Stat3KO background); ablating Stat5 in LepRb neurons also failed to alter energy balance. Importantly, expression of a constitutively-active STAT3 (CASTAT3) in LepRb neurons decreased food intake and body weight and improved metabolic parameters in leptin-deficient (ob/ob) mice, as well as in wild-type animals.

Conclusions: Thus, STAT3 represents the unique STAT protein required for leptin action and STAT3 suffices to mediate important components of leptin action in the absence of other LepRb signals.
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http://dx.doi.org/10.1016/j.molmet.2019.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437596PMC
April 2019

Sex differences in tobacco smokers: Executive control network and frontostriatal connectivity.

Drug Alcohol Depend 2019 02 21;195:59-65. Epub 2018 Dec 21.

McLean Imaging Center, McLean Hospital, 115 Mill St., Belmont, MA, 02478, USA; Department of Psychiatry, Harvard Medical School, 401 Park Drive, Boston, MA, 02215, USA.

Background: Women experience greater difficulty quitting smoking than men, which may be explained by sex differences in brain circuitry underlying cognitive control. Prior work has linked reduced interhemispheric executive control network (ECN) coupling with poor executive function, shorter time to relapse, and greater substance use. Lower structural connectivity between a key ECN hub, the dorsolateral prefrontal cortex (DLPFC), and the dorsal striatum (DS) also contributes to less efficient cognitive control recruitment, and reduced intrahemispheric connectivity between these regions has been associated with smoking relapse. Therefore, sex differences were probed by evaluating interhemispheric ECN and intrahemispheric DLPFC-DS connectivity. To assess the potential sex by nicotine interaction, a pilot sample of non-smokers was evaluated following acute nicotine and placebo administration.

Methods: Thirty-five smokers (19 women) completed one resting state functional magnetic resonance imaging scan. Seventeen non-smokers (8 women) were scanned twice using a repeated measures design where they received 2 and 0 mg nicotine.

Results: In smokers, women had less interhemispheric ECN and DLPFC-DS coupling than men. In non-smokers, there was a drug x sex interaction where women, relative to men, had weaker ECN coupling following nicotine but not placebo administration.

Conclusions: The current work indicates that nicotine-dependent women, versus men, have weaker connectivity in brain networks critically implicated in cognitive control. How these connectivity differences contribute to the behavioral aspects of smoking requires more testing. However, building on the literature, it is likely these deficits in functional connectivity contribute to the lower abstinence rates noted in women relative to men.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625360PMC
February 2019

Lateral Hypothalamic Mc3R-Expressing Neurons Modulate Locomotor Activity, Energy Expenditure, and Adiposity in Male Mice.

Endocrinology 2019 02;160(2):343-358

Division of Endocrinology, Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan.

The central melanocortin system plays a crucial role in the control of energy balance. Although the decreased energy expenditure and increased adiposity of melanocortin-3 receptor (Mc3R)-null mice suggest the importance of Mc3R-regulated neurons in energy homeostasis, the roles for specific subsets of Mc3R neurons in energy balance have yet to be determined. Because the lateral hypothalamic area (LHA) contributes to the control of energy expenditure and feeding, we generated Mc3rcre mice to determine the roles of LHA Mc3R (Mc3RLHA) neurons in energy homeostasis. We found that Mc3RLHA neurons overlap extensively with LHA neuron markers that contribute to the control of energy balance (neurotensin, galanin, and leptin receptor) and project to brain areas involved in the control of feeding, locomotion, and energy expenditure, consistent with potential roles for Mc3RLHA neurons in these processes. Indeed, selective chemogenetic activation of Mc3RLHA neurons increased locomotor activity and augmented refeeding after a fast. Although the ablation of Mc3RLHA neurons did not alter food intake, mice lacking Mc3RLHA neurons displayed decreased energy expenditure and locomotor activity, along with increased body mass and adiposity. Thus, Mc3R neurons lie within LHA neurocircuitry that modulates locomotor activity and energy expenditure and contribute to energy balance control.
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http://dx.doi.org/10.1210/en.2018-00747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937456PMC
February 2019

Defined Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State.

Cell Metab 2019 03 21;29(3):681-694.e5. Epub 2018 Nov 21.

Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD 20892, USA; National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD 21224, USA. Electronic address:

Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry, electrophysiology, immunohistochemistry, and neural manipulation strategies, we determined the population dynamics of four molecularly delineated PVH subsets implicated in feeding behavior: glucagon-like peptide 1 receptor (PVH), melanocortin-4 receptor (PVH), oxytocin (PVH), and corticotropin-releasing hormone (PVH). We identified both calorie- and state-dependent sustained activity increases and decreases in PVH and PVH populations, respectively, while observing transient bulk changes of PVH, but no response in PVH, neurons to food. Furthermore, we highlight the role of PVH neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVH and PVH, but not PVH PVH neurons, in body weight maintenance.
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http://dx.doi.org/10.1016/j.cmet.2018.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402975PMC
March 2019

Specific subpopulations of hypothalamic leptin receptor-expressing neurons mediate the effects of early developmental leptin receptor deletion on energy balance.

Mol Metab 2018 08 6;14:130-138. Epub 2018 Jun 6.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

Objective: To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons (e.g., arcuate nucleus (ARC) Pomc- or Agrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolic dysfunction. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance.

Methods: We generated new mouse lines deleted for LepRb in ARC Ghrh neurons or in Htr2c neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells.

Results: The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc, Agrp, Ghrh, or Htr2c neurons minimally altered energy balance.

Conclusions: Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH.
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http://dx.doi.org/10.1016/j.molmet.2018.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034096PMC
August 2018

Liraglutide Modulates Appetite and Body Weight Through Glucagon-Like Peptide 1 Receptor-Expressing Glutamatergic Neurons.

Diabetes 2018 08 18;67(8):1538-1548. Epub 2018 May 18.

Department of Pediatrics, University of Michigan, Ann Arbor, MI

Glucagon-like peptide 1 receptor (GLP-1R) agonists are U.S. Food and Drug Administration-approved weight loss drugs. Despite their widespread use, the sites of action through which GLP-1R agonists (GLP1RAs) affect appetite and body weight are still not fully understood. We determined whether GLP-1Rs in either GABAergic or glutamatergic neurons are necessary for the short- and long-term effects of the GLP1RA liraglutide on food intake, visceral illness, body weight, and neural network activation. We found that mice lacking GLP-1Rs in -expressing GABAergic neurons responded identically to controls in all parameters measured, whereas deletion of GLP-1Rs in -expressing glutamatergic neurons eliminated liraglutide-induced weight loss and visceral illness and severely attenuated its effects on feeding. Concomitantly, deletion of GLP-1Rs from glutamatergic neurons completely abolished the neural network activation observed after liraglutide administration. We conclude that liraglutide activates a dispersed but discrete neural network to mediate its physiological effects and that these effects require GLP-1R expression on glutamatergic but not GABAergic neurons.
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http://dx.doi.org/10.2337/db17-1385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054439PMC
August 2018

A hypothalamic circuit for the circadian control of aggression.

Nat Neurosci 2018 05 9;21(5):717-724. Epub 2018 Apr 9.

Department of Neurology, Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZ) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZ neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZ transmission phase-dependently increases aggression. Finally, SPZ-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.
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http://dx.doi.org/10.1038/s41593-018-0126-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920747PMC
May 2018

Defining the Transcriptional Targets of Leptin Reveals a Role for in Leptin Action.

Diabetes 2018 06 13;67(6):1093-1104. Epub 2018 Mar 13.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI

Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient ( mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor in LepRb neurons. Furthermore, ablation of from LepRb neurons (Atf3KO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including , which represents a cellular mediator of leptin action.
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http://dx.doi.org/10.2337/db17-1395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961413PMC
June 2018

Identification of Genes Enriched in GnRH Neurons by Translating Ribosome Affinity Purification and RNAseq in Mice.

Endocrinology 2018 04;159(4):1922-1940

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.

Gonadotropin-releasing hormone (GnRH) neurons are a nexus of fertility regulation. We used translating ribosome affinity purification coupled with RNA sequencing to examine messenger RNAs of GnRH neurons in adult intact and gonadectomized (GDX) male and female mice. GnRH neuron ribosomes were tagged with green fluorescent protein (GFP) and GFP-labeled polysomes isolated by immunoprecipitation, producing one RNA fraction enhanced for GnRH neuron transcripts and one RNA fraction depleted. Complementary DNA libraries were created from each fraction and 50-base, paired-end sequencing done and differential expression (enhanced fraction/depleted fraction) determined with a threshold of >1.5- or <0.66-fold (false discovery rate P ≤ 0.05). A core of ∼840 genes was differentially expressed in GnRH neurons in all treatments, including enrichment for Gnrh1 (∼40-fold), and genes critical for GnRH neuron and/or gonadotrope development. In contrast, non-neuronal transcripts were not enriched or were de-enriched. Several epithelial markers were also enriched, consistent with the olfactory epithelial origins of GnRH neurons. Interestingly, many synaptic transmission pathways were de-enriched, in accordance with relatively low innervation of GnRH neurons. The most striking difference between intact and GDX mice of both sexes was a marked downregulation of genes associated with oxidative phosphorylation and upregulation of glucose transporters in GnRH neurons from GDX mice. This may suggest that GnRH neurons switch to an alternate fuel to increase adenosine triphosphate production in the absence of negative feedback when GnRH release is elevated. Knowledge of the GnRH neuron translatome and its regulation can guide functional studies and can be extended to disease states, such as polycystic ovary syndrome.
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http://dx.doi.org/10.1210/en.2018-00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287592PMC
April 2018

Essential Role for Hypothalamic Calcitonin Receptor‒Expressing Neurons in the Control of Food Intake by Leptin.

Endocrinology 2018 04;159(4):1860-1872

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.

The adipocyte-derived hormone leptin acts via its receptor (LepRb) on central nervous system neurons to communicate the repletion of long-term energy stores, to decrease food intake, and to promote energy expenditure. We generated mice that express Cre recombinase from the calcitonin receptor (Calcr) locus (Calcrcre mice) to study Calcr-expressing LepRb (LepRbCalcr) neurons, which reside predominantly in the arcuate nucleus (ARC). Calcrcre-mediated ablation of LepRb in LepRbCalcrknockout (KO) mice caused hyperphagic obesity. Because LepRb-mediated transcriptional control plays a crucial role in leptin action, we used translating ribosome affinity purification followed by RNA sequencing to define the transcriptome of hypothalamic Calcr neurons, along with its alteration in LepRbCalcrKO mice. We found that ARC LepRbCalcr cells include neuropeptide Y (NPY)/agouti-related peptide (AgRP)/γ-aminobutyric acid (GABA) ("NAG") cells as well as non-NAG cells that are distinct from pro-opiomelanocortin cells. Furthermore, although LepRbCalcrKO mice exhibited dysregulated expression of several genes involved in energy balance, neither the expression of Agrp and Npy nor the activity of NAG cells was altered in vivo. Thus, although direct leptin action via LepRbCalcr cells plays an important role in leptin action, our data also suggest that leptin indirectly, as well as directly, regulates these cells.
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http://dx.doi.org/10.1210/en.2017-03259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888224PMC
April 2018

Bone Health and Endocrine Comorbidities in Pediatric Epilepsy.

Semin Pediatr Neurol 2017 11 14;24(4):301-309. Epub 2017 Oct 14.

Divisions of Pediatric Neurology, Department of Pediatrics, University of Michigan, Ann Arbor, MI.

Antiseizure medications and dietary therapies have associated effects on the endocrine system. We provided an overview of the relationship between epilepsy treatment and bone health in children with epilepsy. Additionally, we discussed the effects of epilepsy treatment on other endocrine systems including thyroid function, growth, reproduction, and weight. The effect of epilepsy on bone health is multifactorial; there are direct and indirect effects of medication and dietary treatments as well as a decrease in physical activity, decreased sunlight exposure, decreased vitamin D levels, and additional comorbidities. Some medications have a greater effect on vitamin D and bone health than others, however all antiseizure medical treatments are associated with lower vitamin D levels in pediatric patients. We have provided practical suggestions for vitamin D surveillance in children with epilepsy as well as replacement strategies. Children with epilepsy have an increased likelihood of additional endocrine disorders including subclinical hypothyroidism, decreased growth, weight abnormalities, reproductive and sexual dysfunction. To a great extent, this is medication specific. Though more studies are needed to elucidate optimal treatment and monitoring of bone health and other endocrinopathies in children with epilepsy, it is critical that caregivers pay close attention to these issues to provide optimal comprehensive care to their patients.
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http://dx.doi.org/10.1016/j.spen.2017.10.005DOI Listing
November 2017