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Non-caloric regulation of food intake
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Food intake is shaped by environmental, endocrine, metabolic, and reward-related signals. A change in appetite is an outcome of integration of the relevant external and internal stimuli. While the main purpose of eating is to reverse a negative energy balance, mechanisms protecting homeostasis change appetite for other reasons. This thesis examines the role of select brain mechanisms in regulating consumption driven by aspects other than energy.

In paper I, an increased percentage of c-Fos positive OT neurons was observed after mice ingested sucrose, while no change was found after Intralipid intake. Given a choice between isocaloric sugar and Intralipid solutions, mice injected with an OT receptor antagonist increase their preference for sucrose, while total calorie intake remains unchanged, suggesting that OT prevents overconsumption of sugar.

Paper II addresses whether MCH, which has anxiolytic properties and mediates reward-motivated feeding, has the ability to alleviate conditioned taste aversion in rats. We found that while mRNA expression of MCH and its receptor are changed in aversive animals, central injections of MCH do not prevent the acquisition of aversion, nor do they affect the rate of extinction of the taste aversion.

Paper III describes evidence that the N/OFQ system facilitates food intake by alleviating aversive responsiveness. Blocking the NOP receptor delays extinction of aversion and reduces food intake in hungry rats.

Paper IV reports that leucine ingestion increases mRNA expression levels of genes known to mediate reward, as well as orexigenic gene expression in the nucleus accumbens (Nacc), a key component of the reward circuit. Adding leucine to drinking water increases activity of the reward system, which possibly contributes to the pleasure of consumption.

A separate approach using Drosophila melanogaster is introduced in paper V which provides evidence that knocking down the gene for the transcription factor Ets96B during development results in a simultaneous disruption in sleep patterns and appetite, thus highlighting the interplay between these physiological parameters.

We conclude that OT, MCH, N/OFQ and Ets96B belong to mechanisms regulating food intake for reasons other than energy balance. Composition of food and negative associations with diets affect neural networks controlling appetite.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1007
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
URN: urn:nbn:se:uu:diva-223809ISBN: 978-91-554-8966-3 (print)OAI: oai:DiVA.org:uu-223809DiVA: diva2:714279
Public defence
2014-06-13, B:21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-05-23 Created: 2014-04-25 Last updated: 2014-06-30
List of papers
1. Molecular, Immunohistochemical, and Pharmacological Evidence of Oxytocin's Role as Inhibitor of Carbohydrate But Not Fat Intake
Open this publication in new window or tab >>Molecular, Immunohistochemical, and Pharmacological Evidence of Oxytocin's Role as Inhibitor of Carbohydrate But Not Fat Intake
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2010 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 151, no 10, 4736-4744 p.Article in journal (Refereed) Published
Abstract [en]

Oxytocin (OT) facilitates feeding termination stemming from high osmolality, stomach distention, and malaise. Recent knockout (KO) studies suggested a crucial function for OT in carbohydrate intake: OT-/- mice had increased preference for carbohydrates, including sucrose, but not fat (Intralipid). In striking contrast, sugar appetite was unaffected in the OT receptor KO mouse; data from wild-type animals have been insufficient. Therefore, we examined the involvement of OT in the regulation of sucrose vs. fat intake in C57BL/6 mice that served as a background KO strain. We exposed mice to a meal of sucrose or Intralipid and determined that the percentage of c-Fos-immunoreactive paraventricular hypothalamic OT neurons was elevated at termination of intake of either of the tastants, but this increase was 2-fold higher in sucrose-fed mice. A 48-h exposure to sucrose compared with Intralipid caused up-regulation of OT mRNA, whereas inherent individual preferences for sucrose vs. fat were not associated with differences in baseline OT expression as established with quantitative PCR. We found that L-368,899, an OT receptor antagonist, increased sugar intake when sucrose was presented alone or concurrently with Intralipid; it had no effect on Intralipid or total calorie consumption. L-368,899 affected Fos immunoreactivity in the paraventricular hypothalamus, arcuate nucleus, amygdala, and nucleus of the solitary tract, areas involved in aversion, satiety, and reward. This pattern serves as neuroanatomical basis of OT's complex role in food intake, including sucrose intake. The current findings expand our knowledge on OT and suggest that it acts as a carbohydrate-specific inhibitor of feeding. (Endocrinology 151: 4736-4744, 2010)

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-134798 (URN)10.1210/en.2010-0151 (DOI)000282005700016 ()
Available from: 2010-12-01 Created: 2010-12-01 Last updated: 2017-12-12Bibliographically approved
2. Central nociceptin/orphanin FQ system elevates food consumption by both increasing energy intake and reducing aversive responsiveness
Open this publication in new window or tab >>Central nociceptin/orphanin FQ system elevates food consumption by both increasing energy intake and reducing aversive responsiveness
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2010 (English)In: American Journal of Physiology. Regulatory Integrative and Comparative Physiology, ISSN 0363-6119, E-ISSN 1522-1490, Vol. 299, no 2, R655-R663 p.Article in journal (Refereed) Published
Abstract [en]

Nociceptin/orphanin FQ (N/OFQ), the nociceptin opioid peptide (NOP) receptor ligand, increases feeding when injected centrally. Initial data suggest that N/OFQ blocks the development of a conditioned taste aversion (CTA). The current project further characterized the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodology. We determined that the same low dose of the NOP antagonist [Nphe(1)]N/OFQ(1-13)NH(2) delivered via the lateral ventricle diminishes both N/OFQ- and deprivation-induced feeding. This anorexigenic effect did not stem from aversive consequences, as the antagonist did not cause the development of a CTA. When [Nphe(1)]N/OFQ(1-13)NH(2) was administered with LiCl, it moderately delayed extinction of the LiCl-induced CTA. Injection of LiCl + antagonist compared with LiCl alone generated an increase in c-Fos immunoreactivity in the central nucleus of the amygdala. The antagonist alone elevated Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, and central nucleus of the amygdala. Hypothalamic NOP mRNA levels were decreased during energy intake restriction induced by aversion, as well as in non-CTA rats food-restricted to match CTA-reduced consumption. Brain stem NOP was upregulated only in aversion. Prepro-N/OFQ mRNA showed a trend toward upregulation in restricted rats (P = 0.068). We conclude that the N/OFQ system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially tainted food.

Keyword
food intake, conditioning, hypothalamus, brain stem, amygdala, lithium chloride, NOP receptor, ORL1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-135060 (URN)10.1152/ajpregu.00556.2009 (DOI)000280569800028 ()20427724 (PubMedID)
Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2017-12-12Bibliographically approved
3. Expression levels of genes encoding melanin concentrating hormone (MCH) and MCH receptor change in taste aversion, but MCH injections do not alleviate aversive responses
Open this publication in new window or tab >>Expression levels of genes encoding melanin concentrating hormone (MCH) and MCH receptor change in taste aversion, but MCH injections do not alleviate aversive responses
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2012 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 100, no 3, 581-586 p.Article in journal (Refereed) Published
Abstract [en]

Melanin concentrating hormone (MCH) stimulates feeding driven by energy needs and reward and modifies anxiety behavior. Orexigenic peptides of similar characteristics, including nociceptin/orphanin FQ Agouti-related protein and opioids, increase consumption also by reducing avoidance of potentially tainted food in animals displaying a conditioned taste aversion (CTA). Herein, using real-time PCR, we assessed whether expression levels of genes encoding MCH and its receptor, MCHR1, were affected in CTA in the rat. We also investigated whet her injecting MCH intracerebroventricularly (ICV) during the acquisition and retrieval of LiCl-induced CTA, would alleviate aversive responses. MCHR1 gene was upregulated in the hypothalamus and brain stem of aversive animals. MCH mRNA was significantly higher in the hypothalamus, whereas a strong trend suggesting upregulation of MCH and MCHR1 genes was detected in the amygdala. Despite these expression changes associated with aversion, MCH injected prior to the induction of CTA with LiCl as well as later, during the CTA retrieval upon subsequent presentations of the aversive tastant, did not reduce the magnitude of CTA. We conclude that MCH and its receptor form an orexigenic system whose expression is affected in CTA. This altered MCH expression may contribute to tastant-targeted hypophagia in CTA. However, changing the MCH tone in the brain by exogenous peptide was insufficient to prevent the onset or facilitate extinction of Lid-induced CTA. This designates MCH as one of many accessory molecules associated with shaping an aversive response, but not a critical one for LiCl-dependent CFA to occur.

Keyword
Feeding, Preference, Avoidance, Anorexia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-169983 (URN)10.1016/j.pbb.2011.08.009 (DOI)000300074800033 ()
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved
4. Leucine changes reward-related gene expression and neuronal activity in the hypothalamus and nucleus accumbens
Open this publication in new window or tab >>Leucine changes reward-related gene expression and neuronal activity in the hypothalamus and nucleus accumbens
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The branched-chain amino acid leucine has been shown to have satiating effects when administered centrally. However, studies on how oral administration of leucine affects appetite shown disparate effects ranging from orexigenic to anorexigenic. To shed more light on the effects of ingested leucine on the components of the forebrain circuitry  that govern feeding for hunger versus reward, we studied changes in c-Fos immunoreactivity (IR) immediately after 2-h 1.5 w/v % leucine vs water exposure and used qPCR to analyze relevant feeding-related gene transcripts in mice consuming leucine for 48 h.Leucine caused an increase in c-Fos IR in the arcuate nucleus and a decrease in the paraventricular nucleus whereas a trend towards an increase was detected in the nucleus accumbens shell. We found an increased expression of the µ-opioid receptor (MOR) in the Acb and δ-opioid receptor mRNA in the hypothalamus. Furthermore, expression of anorexigenic genes cocaine- and amphetamine-regulated transcript (CART), oxytocin (OXY) and arginine vasopressin (AVP) was downregulated in the Acb, and CRH expression was elevated in the hypothalamus of mice fed with leucine. Our results indicate that ingested leucine affects both the hunger- and reward-related circuits, which likely underlies the mixed orexigenic and anorexigenic outcomes of this amino acid’s consumption.

National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-223807 (URN)
Available from: 2014-04-25 Created: 2014-04-25 Last updated: 2014-06-30
5. The Drosophila ETV5 homologue Ets96B modulates feeding behavior
Open this publication in new window or tab >>The Drosophila ETV5 homologue Ets96B modulates feeding behavior
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Recent genome-wide association studies (GWAS) have linked the PEA3-family member ets variant 5 (ETV5) to BMI and obesity, yet how this gene regulates metabolic homeostasis is still not clear. The PEA3-family was found to be remarkably conserved and present in species from Drosophila melanogaster to humans. The Drosophila PEA3-family homologue Ets96B is expressed in both the larval and adult central nervous system and, similar to mammalian ETV5, is highly expressed in the testis. In the current study we demonstrate that the obesity-linked homologue Ets96B regulates feeding behavior, as well as lipid storage in adult flies. Furthermore, we demonstrate this is a developmental phenotype. Of notable interest, when Ets96B was knocked down in the entire CNS or specifically in Ets96B expressing cells from embryogenesis, feeding behavior and lipid storage phenotypes were observed; yet when Ets96B was specifically knocked down in the adult CNS there was no effect on feeding, while an opposite effect on lipid storage was revealed. From these data we speculate that loss of Ets96B may disrupt CNS development, leading to metabolic homeostatic phenotypes.

National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-223808 (URN)
Available from: 2014-04-25 Created: 2014-04-25 Last updated: 2014-06-30

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