Expression of a hypomorphic Pomc allele alters leptin dynamics during late pregnancy

Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) are essential for normal energy homeostasis. Maximal ARC Pomc transcription is dependent on neuronal Pomc enhancer 1 (nPE1), located 12 kb upstream from the promoter. Selective deletion of nPE1 in mice decreases ARC Pomc expression by 70%, sufficient to induce mild obesity. Because nPE1 is located exclusively in the genomes of placental mammals, we questioned whether its hypomorphic mutation would also alter placental Pomc expression and the metabolic adaptations associated with pregnancy and lactation. We assessed placental development, pup growth, circulating leptin and expression of Pomc, Agrp and alternatively spliced leptin receptor (LepR) isoforms in the ARC and placenta of Pomc∆1/∆1 and Pomc+/+ dams. Despite indistinguishable body weights, lean mass, food intake, placental histology and Pomc expression and overall pregnancy outcomes between the genotypes, Pomc ∆1/∆1 females had increased pre-pregnancy fat mass that paradoxically decreased to control levels by parturition. However, Pomc∆1/∆1 dams had exaggerated increases in circulating leptin, up to twice of that of the typically elevated levels in Pomc+/+ mice at the end of pregnancy, despite their equivalent fat mass. Pomc∆1/∆1dams also had increased placental expression of soluble leptin receptor (LepRe), although the protein levels of LEPRE in circulation were the same as Pomc+/+ controls. Together, these data suggest that the hypomorphic Pomc∆1/∆1 allele is responsible for the perinatal super hyperleptinemia of Pomc∆1/∆1 dams, possibly due to upregulated leptin secretion from individual adipocytes.

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Central growth hormone action regulates metabolism during pregnancy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00229.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. E925-E940 ◽

Cited By ~ 10

Author(s):

Pryscila D. S. Teixeira ◽

Gisele C. Couto ◽

Isadora C. Furigo ◽

Edward O. List ◽

John J. Kopchick ◽

...

Keyword(s):

Growth Hormone ◽

Food Intake ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Late Pregnancy ◽

Metabolic Adaptations ◽

Growth Hormone Action ◽

Lower Glucose ◽

Pregnancy And Lactation ◽

Glucose Stimulated Insulin Secretion

The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)–expressing neurons, in leptin receptor (LepR)–expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other “gestational hormones” to prepare the maternal organism for the metabolic demands of the offspring.

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Expression of multidrug resistance-associated protein 2 in small intestine from pregnant and postpartum rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.280.6.g1261 ◽

2001 ◽

Vol 280 (6) ◽

pp. G1261-G1273 ◽

Cited By ~ 47

Author(s):

Aldo D. Mottino ◽

Tim Hoffman ◽

Lothar Jennes ◽

Jingsong Cao ◽

Mary Vore

Keyword(s):

Small Intestine ◽

Multidrug Resistance ◽

Blot Analysis ◽

Late Pregnancy ◽

Female Rats ◽

Intestinal Cell ◽

Pregnant Rats ◽

Control Female ◽

Protein Levels ◽

Pregnancy And Lactation

We analyzed the expression of multidrug resistance-associated protein 2 (mrp2) in the small intestine of control female rats and in rats during late pregnancy (19–20 days of pregnancy) and lactation (2–4, 10–14, and 21 days after delivery). Western blot analysis was performed on brush-border membranes prepared from different regions of the small intestine. Expression of mrp2 was maximal in the proximal segments for all experimental groups, was preserved in pregnant rats, and increased by 100% in postpartum rats by late lactation with respect to control animals. Northern blot analysis of mrp2 mRNA revealed a positive correlation with protein levels. Transport of S-glutathione-dinitrophenol (DNP-SG) from the intestinal cell to the lumen was analyzed in the everted intestinal sac model. Secretion of DNP-SG was not altered in pregnant rats but increased in lactating animals by late lactation. Intestinal mrp2 mRNA, protein, and transport activity are increased in lactating rats, suggesting that this may represent an adaptive mechanism to minimize the toxicity of dietary xenobiotics in response to increased postpartum food consumption.

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Voluntary Exercise Improves High-Fat Diet-Induced Leptin Resistance Independent of Adiposity

Endocrinology ◽

10.1210/en.2010-1340 ◽

2011 ◽

Vol 152 (7) ◽

pp. 2655-2664 ◽

Cited By ~ 53

Author(s):

Kimberly A. Krawczewski Carhuatanta ◽

Giovanna Demuro ◽

Matthias H. Tschöp ◽

Paul T. Pfluger ◽

Stephen C. Benoit ◽

...

Keyword(s):

Fat Mass ◽

High Fat Diet ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Voluntary Exercise ◽

Leptin Resistance ◽

Hypothalamic Nucleus ◽

High Fat ◽

Ventromedial Hypothalamic Nucleus ◽

Obesity In Mice

The efficacy of exercise as primary prevention of obesity is the subject of intense investigation. Here, we show that voluntary exercise in a mouse strain susceptible to diet-induced obesity (C57B6J) decreases fat mass and increases energy expenditure. In addition, exercise attenuates obesity in mice fed a high-fat diet (HFD). Using FosB immunoreactivity as a marker of chronic neuronal activation, we found that exercise activates leptin receptor-positive neurons in the ventromedial hypothalamic nucleus, involved in homeostatic control of energy balance. FosB immunoreactivity in the ventromedial hypothalamic nucleus is decreased in sedentary mice exposed to HFD but is increased in exercised mice independent of adiposity. To determine whether the antiobesity effects of voluntary exercise improve central nervous system (CNS) leptin action, we measured the anorectic and weight reducing effects of intracerebroventricular (ICV) leptin in sedentary and exercised mice exposed to HFD (EH), as well as in sedentary mice that have been calorie restricted (SR) to match the fat mass of EH mice. ICV leptin was ineffective in lowering food intake and body weight (BW) in sedentary mice exposed to HFD mice. The anorectic potency of leptin was partially restored in EH and SR groups. However, ICV leptin significantly lowered BW in EH but not SR mice. Thus, exercise leads to the maintenance of a lower BW and leaner composition, as well as to improved CNS leptin action, independent of fat mass. These results support the notion that physical exercise directly influences the responsiveness of the CNS circuits involved in energy homeostasis by allowing the defense of a lowered BW.

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Transcript abundances of the prolactin receptor, the leptin receptor and their major suppressor in the sheep mammary gland during pregnancy and lactation

Annals of Animal Science ◽

10.2478/aoas-2020-0035 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Malgorzata Szczesna ◽

Katarzyna Kirsz ◽

Michal Nowakowski ◽

Dorota A. Zieba

Keyword(s):

Mammary Gland ◽

Leptin Receptor ◽

Prolactin Receptor ◽

Signal Transduction Pathway ◽

Late Pregnancy ◽

Transcript Level ◽

Transcript Abundance ◽

Cytokine Signaling ◽

Pregnancy And Lactation ◽

Plasma Prl

AbstractThis study aimed to expand the knowledge of the interactions between prolactin (PRL) and leptin in the ovine mammary gland during pregnancy and lactation; we examined the mRNA expression of prolactin receptor (PRLR), the long form of the leptin receptor (LRb) and suppressor of cytokine signaling (SOCS)-3 in mammary gland biopsies collected on days 60, 90 and 120 of pregnancy and on days 30, 60 and 90 of lactation (n = 6 for each time point), along with the plasma PRL and leptin concentrations. The PRL concentrations were stable throughout pregnancy and increased during lactation. The plasma leptin concentrations were comparable among nonpregnant, early-pregnant, late-pregnant and lactating ewes, but this metric peaked during mid-pregnancy. Expression of PRLR and SOCS-3 in the mammary gland fluctuated during the transition from pregnancy to lactation, and differences in LRb expression occurred during the late stages of lactation. The LRb transcript abundance was approximately 31 times higher in ewes on day 60 of lactation than in early-lactating ewes. Expression of SOCS-3 mRNA in biopsies gradually decreased over the course of pregnancy and reached a minimum value during late pregnancy. After lambing, the transcript level of SOCS-3 increased and peaked on day 60 of lactation. During pregnancy, the plasma PRL concentration positively correlated with the abundances of PRLR (r = 0.971, P < 0.01) and SOCS-3 (r = 0.818, P < 0.05). Positive correlations were also observed between the transcript abundances of SOCS-3 and LRb (r = 0.854, P < 0.05). The variations observed in the plasma PRL and leptin concentrations and the changes in expression of key leptin and PRL signal transduction pathway components, such as PRLR, LRb and SOCS-3, indicate that the efficacies of both hormone actions are modulated in a multilevel manner throughout pregnancy and lactation. These interactions may regulate the ability of the mammary gland to respond to current energy requirements and challenges, thus affecting milk yield and lactation duration.

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Astaxanthin Exerts Anabolic Effects via Pleiotropic Modulation of the Excitable Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms23020917 ◽

2022 ◽

Vol 23 (2) ◽

pp. 917

Author(s):

Mónika Gönczi ◽

Andrea Csemer ◽

László Szabó ◽

Mónika Sztretye ◽

János Fodor ◽

...

Keyword(s):

Skeletal Muscle ◽

Food Intake ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Fatty Acid Biosynthesis ◽

Synaptic Activity ◽

Systematic Analysis ◽

Protein Levels ◽

General Metabolism ◽

Hypothalamic Arcuate Nucleus

Astaxanthin is a lipid-soluble carotenoid influencing lipid metabolism, body weight, and insulin sensitivity. We provide a systematic analysis of acute and chronic effects of astaxanthin on different organs. Changes by chronic astaxanthin feeding were analyzed on general metabolism, expression of regulatory proteins in the skeletal muscle, as well as changes of excitation and synaptic activity in the hypothalamic arcuate nucleus of mice. Acute responses were also tested on canine cardiac muscle and different neuronal populations of the hypothalamic arcuate nucleus in mice. Dietary astaxanthin significantly increased food intake. It also increased protein levels affecting glucose metabolism and fatty acid biosynthesis in skeletal muscle. Inhibitory inputs innervating neurons of the arcuate nucleus regulating metabolism and food intake were strengthened by both acute and chronic astaxanthin treatment. Astaxanthin moderately shortened cardiac action potentials, depressed their plateau potential, and reduced the maximal rate of depolarization. Based on its complex actions on metabolism and food intake, our data support the previous findings that astaxanthin is suitable for supplementing the diet of patients with disturbances in energy homeostasis.

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Reproductive neuronal circuitry in adaptive changes of energy balance

10.1101/2021.09.09.459635 ◽

2021 ◽

Author(s):

Pilhwa Lee ◽

Cristina Sáenz de Miera ◽

Nicole Bellefontaine ◽

Marina A Silveira ◽

Thais T Zampieri ◽

...

Keyword(s):

Dopamine Transporter ◽

Leptin Receptor ◽

Prolactin Receptor ◽

Reproductive Function ◽

Late Pregnancy ◽

High Energy ◽

Metabolic Dysfunction ◽

Adaptive Responses ◽

New Findings ◽

Pregnancy And Lactation

AbstractThe crosstalk between metabolism and reproduction is essential for species survival. When dysfunctional, this interaction may decrease reproductive efficiency, but in physiological conditions of high energy demands, e.g., pregnancy and lactation, it is highly beneficial. Females display adaptive responses that assure offspring survival and health, including increased food intake and suppression of the reproductive function. Some of these physiological responses are modulated by leptin actions in neuronal pathways that are still unclear. The hypothalamic ventral premammillary nucleus (PMv) is a key integrative node of metabolic cues and reproductive status, comprised of either leptin-depolarized or -hyperpolarized neurons. Here, we show that the subset of leptin-hyperpolarized neurons coexpresses dopamine transporter (DAT) and prolactin receptor. DAT expression is higher in prepubertal conditions, when reproductive function is suppressed. These neurons innervate AgRP presynaptic terminals and may potentiate their inhibitory actions on reproduction. We further applied a mathematical model to reconcile our new findings with the current literature and to verify if those neurons are putative components of the metabolic control of reproduction. In our model, leptin-depolarized PMv neurons project to and directly stimulate kisspeptin and gonadotropin releasing hormone (GnRH) neurons. Leptin-hyperpolarized PMv DAT neurons are directly stimulated by prolactin and project to inhibitory control sites. During conditions of high prolactin levels, i.e., late pregnancy and lactation, this pathway may overcome the former, facilitating AgRP actions in the suppression of the reproductive function. Our model also predicts that overstimulation of this pathway may underlie earlier puberty and reproductive deficits observed in conditions of metabolic dysfunction.Significance StatementWomen with excess or low energy stores (e.g., obesity or anorexia) have reproductive deficits, including altered puberty onset, disruption of reproductive cycles and decreased fertility. If able to conceive, they show higher risks of miscarriages and preterm birth. The hypothalamic circuitry controlling the interplay between metabolism and reproduction is undefined. Neurons in the ventral premammillary nucleus express leptin receptor and project to reproductive control sites. Those neurons are essentially glutamatergic, but functionally and phenotypically heterogeneous. They either depolarize or hyperpolarize in response to leptin. We show that leptin-hyperpolarized neurons coexpress dopamine transporter and prolactin receptor, and project to AgRP inhibitory output. Computational modeling was applied to build a neuronal network integrating metabolism and reproduction in typical and dysfunctional physiology.

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The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure

Journal of Endocrinology ◽

10.1677/joe-06-0144 ◽

2007 ◽

Vol 193 (1) ◽

pp. 1-9 ◽

Cited By ~ 47

Author(s):

Hiroyuki Shimizu ◽

Kinji Inoue ◽

Masatomo Mori

Keyword(s):

Energy Expenditure ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Signaling System ◽

Leptin Signaling ◽

Melanocyte Stimulating Hormone ◽

Hypothalamic Nuclei ◽

Hypothalamic Arcuate Nucleus ◽

Melanocortin Signaling ◽

The Brain

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived α-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.

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The Neuronal Actions of Leptin and the Implications for Treating Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph14010052 ◽

2021 ◽

Vol 14 (1) ◽

pp. 52

Author(s):

Kirsty Hamilton ◽

Jenni Harvey

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Hippocampal Formation ◽

Synaptic Function ◽

Receptor Expression ◽

Neuroprotective Actions ◽

Novel Target ◽

Leptin System

It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has a significant impact on hippocampal synaptic function. Thus, cellular and behavioural studies support a cognitive enhancing role for leptin as excitatory synaptic transmission, synaptic plasticity and glutamate receptor trafficking at hippocampal Schaffer collateral (SC)-CA1 synapses are regulated by leptin, and treatment with leptin enhances performance in hippocampus-dependent memory tasks. Recent studies indicate that hippocampal temporoammonic (TA)-CA1 synapses are also a key target for leptin. The ability of leptin to regulate TA-CA1 synapses has important functional consequences as TA-CA1 synapses are implicated in spatial and episodic memory processes. Moreover, degeneration is initiated in the TA pathway at very early stages of Alzheimer’s disease, and recent clinical evidence has revealed links between plasma leptin levels and the incidence of Alzheimer’s disease (AD). Additionally, accumulating evidence indicates that leptin has neuroprotective actions in various AD models, whereas dysfunctions in the leptin system accelerate AD pathogenesis. Here, we review the data implicating the leptin system as a potential novel target for AD, and the evidence that boosting the hippocampal actions of leptin may be beneficial.

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