Activation of leptin receptor-expressing neurons in lateral hypothalamus enhances food-seeking behavior without altering food intake in mice

Oxytocin (OT) is a neuropeptide whose central receptor-mediated actions include reducing food intake. One mechanism of its behavioral action is the amplification of the feeding inhibitory effects of gastrointestinal (GI) satiation signals processed by hindbrain neurons. OT treatment also reduces carbohydrate intake in humans and rodents, and correspondingly, deficits in central OT receptor (OT-R) signaling increase sucrose self-administration. This suggests that additional processes contribute to central OT effects on feeding. This study investigated the hypothesis that central OT reduces food intake by decreasing food seeking and food motivation. As central OT-Rs are expressed widely, a related focus was to assess the role of one or more OT-R-expressing nuclei in food motivation and food-seeking behavior. OT was delivered to the lateral ventricle (LV), nucleus tractus solitarius (NTS), or ventral tegmental area (VTA), and a progressive ratio (PR) schedule of operant reinforcement and an operant reinstatement paradigm were used to measure motivated feeding behavior and food-seeking behavior, respectively. OT delivered to the LV, NTS, or VTA reduced 1) motivation to work for food and 2) reinstatement of food-seeking behavior. Results provide a novel and additional interpretation for central OT-driven food intake inhibition to include the reduction of food motivation and food seeking.

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Activation of Pyramidal Neurons in Mouse Medial Prefrontal Cortex Enhances Food-Seeking Behavior While Reducing Impulsivity in the Absence of an Effect on Food Intake

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2016.00063 ◽

2016 ◽

Vol 10 ◽

Cited By ~ 16

Author(s):

Daniel M. Warthen ◽

Philip S. Lambeth ◽

Matteo Ottolini ◽

Yingtang Shi ◽

Bryan Scot Barker ◽

...

Keyword(s):

Prefrontal Cortex ◽

Food Intake ◽

Medial Prefrontal Cortex ◽

Pyramidal Neurons ◽

Seeking Behavior ◽

Food Seeking

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LH LepR neurons directly drive sustained food seeking behavior after AgRP neuronal deactivation via neuromodulation of NPY

10.1101/2020.10.23.352187 ◽

2020 ◽

Author(s):

Younghee Lee ◽

Ha Young Song ◽

You Bin Kim ◽

Kyu Sik Kim ◽

Dong-Soo Ha ◽

...

Keyword(s):

Feeding Behavior ◽

Leptin Receptor ◽

Feeding Behaviors ◽

Approach Behavior ◽

Food Search ◽

Feeding Experiments ◽

Neuron Activation ◽

Imaging Results ◽

Seeking Behavior ◽

Food Seeking

1.AbstractAgouti-related protein (AgRP) has been believed to be the main driver of feeding behaviors ever since its discovery. However, recent studies using fiber photometry and optogenetics proved that feeding behaviors are not directly driven by AgRP neurons (temporal discrepancy between neuronal activity and behavior). To resolve this paradox, we conducted novel multi-phase feeding experiments to scrutinize the dynamics of AgRP. Fiber photometry study showed that AgRP neurons start to deactivate even before the initiation of the food search phase. Using optogenetics, we could prove that the feeding behavior induced by AgRP neuron activation had substantial temporal delay and the feeding behavior was sustained for substantial time even after cessation of optogenetic activation. These results indicate that AgRP neurons are not the direct driver of feeding behavior and another downstream neuron is the driver of feeding behavior. Leptin receptor (LepR) neurons in the lateral hypothalamus (LH). LH LepR neurons were activated before voluntary food search behavior initiation and showed robust increase after food approach behavior. Artificial activation of LH LepR neurons drives food search and food approach behavior. In accordance, chemogenetic activation of LepR neurons increased food search and food approach behaviors. Lastly, slice calcium imaging results showed the possibility that NPY from the AgRP neurons could be the downstream neuromodulator of AgRP neuron, driving LH LepR neuron activation. Overall, our study shows that AgRP neurons are not the direct drivers of feeding behavior, whereas LH LepR neurons directly drive sustained food seeking behavior.

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High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring

Nutrients ◽

10.3390/nu13051477 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1477

Author(s):

Emanuela Pannia ◽

Rola Hammoud ◽

Ruslan Kubant ◽

Jong Yup Sa ◽

Rebecca Simonian ◽

...

Keyword(s):

Body Weight ◽

Folic Acid ◽

Food Intake ◽

Leptin Receptor ◽

Liver Weight ◽

Female Offspring ◽

Mature Female ◽

Cytokine Signaling ◽

Light Cycle ◽

Energy Regulation

Supplementation with [6S]-5-methyltetrahydrofolic acid (MTHF) is recommended as an alternative to folic acid (FA) in prenatal supplements. This study compared equimolar gestational FA and MTHF diets on energy regulation of female offspring. Wistar rats were fed an AIN-93G diet with recommended (2 mg/kg diet) or 5-fold (5X) intakes of MTHF or FA. At weaning, female offspring were fed a 45% fat diet until 19 weeks. The 5X-MTHF offspring had higher body weight (>15%), food intake (8%), light-cycle energy expenditure, and lower activity compared to 5X-FA offspring (p < 0.05). Both the 5X offspring had higher plasma levels of the anorectic hormone leptin at birth (60%) and at 19 weeks (40%), and lower liver weight and total liver lipids compared to the 1X offspring (p < 0.05). Hypothalamic mRNA expression of leptin receptor (ObRb) was lower, and of suppressor of cytokine signaling-3 (Socs3) was higher in the 5X-MTHF offspring (p < 0.05), suggesting central leptin dysregulation. In contrast, the 5X-FA offspring had higher expression of genes encoding for dopamine and GABA- neurotransmitter receptors (p < 0.01), consistent with their phenotype and reduced food intake. When fed folate diets at the requirement level, no differences were found due to form in the offspring. We conclude that MTHF compared to FA consumed at high levels in the gestational diets program central and peripheral mechanisms to favour increased weight gain in the offspring. These pre-clinical findings caution against high gestational intakes of folates of either form and encourage clinical trials examining their long-term health effects when consumed during pregnancy.

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Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2020-002104 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002104

Author(s):

Kenji Takeda ◽

Hiraku Ono ◽

Ko Ishikawa ◽

Tomohiro Ohno ◽

Jin Kumagai ◽

...

Keyword(s):

Food Intake ◽

Lateral Hypothalamus ◽

Molecular Mechanisms ◽

Intraperitoneal Administration ◽

Adenosine Monophosphate ◽

Sglt2 Inhibitors ◽

Central Administration ◽

Hypothalamic Area ◽

Sodium Glucose Cotransporter ◽

Increase Food Intake

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

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Leptin Receptor Compound Heterozygosity in Humans and Animal Models

International Journal of Molecular Sciences ◽

10.3390/ijms22094475 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4475

Author(s):

Claudia Berger ◽

Nora Klöting

Keyword(s):

Food Intake ◽

Animal Models ◽

Leptin Receptor ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Compound Heterozygosity ◽

Therapy Options ◽

Obese Phenotype ◽

Deficient Mice

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.

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SAT-604 The Role of the Focal Adhesion Kinase Family in Leptin Receptor Signaling

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.666 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Colleen Hadley ◽

Isin Cakir ◽

Roger D Cone

Keyword(s):

Food Intake ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Leptin Receptor ◽

Kinase Activity ◽

Cytokine Receptor ◽

Receptor Signaling ◽

Kinase Family ◽

Stat3 Phosphorylation

Abstract Overweight and obesity are global concerns affecting nearly one third of the world population. These conditions are characterized by increased adiposity and are accompanied by a proportional increase in circulating leptin, an anorexigenic adipokine. Leptin is responsible for signaling peripheral energy status to the central nervous system to modulate food intake and energy expenditure. As such, neurons within the hypothalamus expressing the long isoform of leptin receptor (LepRb), a type I cytokine receptor, are primarily responsible for mediating the effects of leptin, which signal predominantly through the JAK2-STAT3 transduction mechanism. STAT3 is a latent transcription factor activated upon phosphorylation, which triggers its homodimerization and nuclear translocation. Evidence, however, for JAK2-independent, STAT3-dependent leptin receptor signaling mechanisms exist. FAK (focal adhesion kinase, Ptk2) and Pyk2 (protein tyrosine kinase 2b, Ptk2b) are a subset of nonreceptor protein tyrosine kinases and comprise the focal adhesion kinase family. FAK and Pyk2 are implicated in the regulation of cytokine receptor signaling. Furthermore, Pyk2 knockout mice have an obesity prone phenotype. Here, we studied the role of the focal adhesion kinases in leptin receptor signaling using genetic and pharmacological approaches. We found that overexpression of Pyk2 or FAK increased STAT3 phosphorylation (activation). Overexpression of a FAK or Pyk2 construct with impaired kinase activity, however, attenuated STAT3 phosphorylation, suggesting the increase in STAT3 phosphorylation is largely dependent upon kinase activity of FAK/Pyk2. Treatment of cells with a small molecule dual inhibitor of FAK and Pyk2 (PF431396) attenuated leptin-induced STAT3 phosphorylation in a mouse hypothalamic cell line. Importantly, this effect is independent of JAK2, as PF treatment of two independent JAK2-deficient cell lines exhibited similar attenuation of leptin-induced STAT3 phosphorylation. To assess the physiological relevance of FAK/Pyk2 in leptin receptor signaling in vivo, we administered PF compound to the lateral ventricle of 24-hour fasted lean wild-type mice followed by peripheral leptin administration. Intracerebroventricular (ICV) administration of PF suppressed the anorectic effect of leptin as evidenced by impaired inhibition of food intake upon refeeding. Accordingly, analysis of total hypothalamic lysates from these mice showed ICV PF impaired leptin-induced STAT3 phosphorylation. Taken together, these data suggest that Pyk2 and/or FAK play a role in leptin signal transduction.

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Adrenergic Stimulation of the Rat Diencephalon and its Effect on Food Intake and Hoarding Activity

Quarterly Journal of Experimental Psychology ◽

10.1080/00335557043000050 ◽

1970 ◽

Vol 22 (2) ◽

pp. 125-132 ◽

Cited By ~ 12

Author(s):

J. E. Blundell ◽

L. J. Herberg

Keyword(s):

Electrical Stimulation ◽

Food Intake ◽

Food Deprivation ◽

Lateral Hypothalamus ◽

Adrenergic Stimulation ◽

Feeding Mechanism ◽

Stimulation Of ◽

Nutritional Depletion

The diencephalic area most sensitive to microinjections of noradrenaline lay outside the area of the lateral hypothalamus in which feeding can be produced by electrical stimulation. Injection of either area, including injections that caused increased feeding, failed to have any effect on hoarding activity. Since hoarding can be elicited both by food deprivation and by electrical stimulation of the lateral hypothalamus, these findings indicate biochemical, anatomical and motivational differences between the central feeding mechanism sensitive to adrenergic stimulation, and that responding to electrical stimulation or nutritional depletion. The former mechanism may be disinhibitory; the latter, excitatory.

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Influence of photoperiod and gonadal status on food intake, adiposity, and gene expression of hypothalamic appetite regulators in a seasonal mammal

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00417.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. R242-R252 ◽

Cited By ~ 19

Author(s):

Chantacha Anukulkitch ◽

Alexandra Rao ◽

Frank R. Dunshea ◽

Dominique Blache ◽

Gerald A. Lincoln ◽

...

Keyword(s):

Gene Expression ◽

Food Intake ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Reproductive Axis ◽

Pomc Gene ◽

Gonadal Status ◽

Long Photoperiod ◽

Refractory Phase

We studied the effects of photoperiod on metabolic profiles, adiposity, and gene expression of hypothalamic appetite-regulating peptides in gonad-intact and castrated Soay rams. Groups of five to six animals were studied 6, 18, or 30 wk after switching from long photoperiod (LP: 16 h of light) to short photoperiod (SP: 8 h of light). Reproductive and metabolic indexes were measured in blood plasma. Expression of neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor (ObRb) in the arcuate nucleus was measured using in situ hybridization. Testosterone levels of intact animals were low under LP, increased to a peak at 16 wk under SP, and then declined. Voluntary food intake (VFI) was high under LP in both intact and castrated animals, decreased to a nadir at 12–16 wk under SP, and then recovered, but only in intact rams as the reproductive axis became photorefractory to SP. NPY gene expression varied positively and POMC expression varied negatively with the cycle in VFI, with differences between intact and castrate rams in the refractory phase. ObRb expression decreased under SP, unrelated to changes in VFI. Visceral fat weight also varied between the intact and castrated animals across the cycle. We conclude that 1) photoperiodic changes in VFI reflect changes in NPY and POMC gene expression, 2) changes in ObRb gene expression are not necessarily determinants of changes in VFI, 3) gonadal status affects the pattern of VFI that changes with photoperiod, and 4) in the absence of gonadal factors, animals can eat less but gain adiposity.

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