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Low dose peripheral leptin infusion produces selective activation of ventromedial hypothalamic and hindbrain STAT3
Harris RBS (2023) Low dose peripheral leptin infusion produces selective activation of ventromedial hypothalamic and hindbrain STAT3. Am J Physiol Endocrinol Metab doi: 10.1152/ajpendo.00083.2023 PMID: 37285599
Objective: To show that the deletion of leptin-receptor expressing cells in the ventromedial hypothalamus (VMH) has no effect on basal body weight or body fat mass, but greatly attenuates the inhibition of food intake.
Summary: This study evaluates leptin’s impact on hypothalamic pSTAT3 in leptin-infused versus injected rats. High-dose leptin suppressed food intake and reduced weight and fat mass without affecting energy metrics, with pSTAT3 increases observed in the VMH only during intake suppression and in the nucleus of the solitary tract over both short and extended periods. These results highlight the role of VMH and hindbrain receptors in mediating leptin’s effects on food intake and metabolic changes.
Usage: Leptin-SAP is referenced in Seamon et al 2019: Male Sprague-Dawley rats received bilateral VMH 75 nl injections of 260 ng/microliter of Leptin-SAP (IT-47) or Blank-Saporin (IT-21).
Related Products: Leptin-SAP (Cat. #IT-47), Blank-SAP (Cat. #IT-21)
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Leptin coordinates efferent sympathetic outflow to the white adipose tissue through the midbrain centrally-projecting Edinger-Westphal nucleus in male rats.
Xu L, Füredi N, Lutter C, Geenen B, Pétervári E, Balaskó M, Dénes Á, Kovács KJ, Gaszner B, Kozicz T (2022) Leptin coordinates efferent sympathetic outflow to the white adipose tissue through the midbrain centrally-projecting Edinger-Westphal nucleus in male rats. Neuropharmacology 205:108898. doi: 10.1016/j.neuropharm.2021.108898
Objective: To show that leptin bound to neurons of the Edinger-Westphal nucleus (EWcp) stimulated STAT3 phosphorylation and increases urocortin 1 (Ucn1)-production in a time-dependent manner.
Summary: EWcp/LepRb/Ucn1 neurons respond to leptin signaling as well as control white adipose tissue size and fat metabolism without altering food intake.
Usage: Ablation of EWcp leptin receptor (LepRb) positive neurons with leptin-saporin. Either unconjugated saporin (53 ng in 80 nl MQ, or Leptin-SAP (90 ng in 80 nl MQ, was injected into the rat midbrain.
Related Products: Leptin-SAP (Cat. #IT-47), Saporin (Cat. #PR-01)
Neurodegeneration in the centrally-projecting Edinger-Westphal nucleus contributes to the non-motor symptoms of Parkinson’s disease in the rat
Ujvári B, Pytel B, Márton Z, Bognár M, Kovács LÁ, Farkas J, Gaszner T, Berta G, Kecskés A, Kormos V, Farkas B, Füredi N, Gaszner B (2022) Neurodegeneration in the centrally-projecting Edinger-Westphal nucleus contributes to the non-motor symptoms of Parkinson’s disease in the rat. J Neuroinflammation 19(1):31. doi: 10.1186/s12974-022-02399-w
Objective: To investigate whether neuron loss and alpha-synuclein accumulation in the urocortin 1 containing (UCN1) cells of the centrally-projecting Edinger-Westphal (EWcp) nucleus is associated with anxiety and depression-like state in the rat.
Summary: Neurodegeneration of urocortinergic EWcp contributes to the mood-related non-motor symptoms in toxic models of Parkinson’s disease in the rat.
Usage: Leptin-SAP or unconjugated Saporin (0.08 μl) was injected into the EWcp area. This selective ablation of UCN1 neurons was used to validate the depression-like phenotype in rats. Behavioral, functional–morphological, biochemical and histopathological tools were used to test the motor coordination, mood status as well as morphological changes in the brain.
Related Products: Saporin (Cat. #PR-01), Leptin-SAP (Cat. #IT-47)
Centrally projecting edinger-westphal nucleus in the control of sympathetic outflow and energy homeostasis
Cano G, Hernan SL, Sved AF (2021) Centrally projecting edinger-westphal nucleus in the control of sympathetic outflow and energy homeostasis. Brain Sci 11(8):1005. doi: 10.3390/brainsci11081005
Objective: To test the hypothesis that Edinger-Westphal nucleus (EWcp) integrates multimodal signals (stress, thermal, metabolic, endocrine, etc.) and modulates the sympathetic output simultaneously to multiple effector organs to maintain energy homeostasis under different conditions that require adjustments of energy demands.
Summary: Besides its role in feeding/metabolic control and addiction, EWcp is involved in several important functions that are ultimately related to different aspects of stress responses, as well as stress coping and adaptation.
Related Products: Leptin-SAP (Cat. #IT-47)
Loss of leptin receptor-expressing cells in the hindbrain decreases forebrain leptin sensitivity.
Harris RBS (2020) Loss of leptin receptor-expressing cells in the hindbrain decreases forebrain leptin sensitivity. Am J Physiol Endocrinol Metab 318(5):E806-E816. doi: 10.1152/ajpendo.00020.2020
Objective: This study tested whether loss of hindbrain leptin receptor signaling changed sensitivity to forebrain leptin.
Summary: Loss of VMH (ventromedial nucleus of hippocampus) leptin receptor-expressing cells prevents weight loss. The integrated response between the hindbrain and forebrain is heavily dependent upon leptin activity in the VMH.
Usage: To test forebrain leptin sensitivity Leptin-SAP and Blank-SAP rats received third ventricle injections of 0, 0.05, 0.1, 0.25 or 0.5 μg leptin.
Related Products: Leptin-SAP (Cat. #IT-47), Blank-SAP (Cat. #IT-21)
Leptin receptor activity in the nucleus of the solitary tract increases forebrain leptin sensitivity
Harris RB (2019) Leptin receptor activity in the nucleus of the solitary tract increases forebrain leptin sensitivity. Neuroscience 2019 Abstracts 591.04. Society for Neuroscience, Chicago, IL.
Summary: We previously reported that fourth ventricle infusions of leptin that cause weight loss are associated with an increase in hypothalamic phosphorylation of signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor (ObRb) activation, implying an integrated response to central leptin. This study tested the impact of ObRb activity in the nucleus of the solitary tract (NTS) on sensitivity to leptin in the forebrain. Leptin-Saporin (Lep-Sap) injections were used to delete ObR- expressing neurons in the NTS of 300g male Sprague Dawley rats. Controls were injected with Blank-Saporin (Blk-Sap). Loss of NTS ObR was confirmed with RNAScope in situ hybridization and pSTAT3 response to peripheral leptin in representative Lep- Sap rats. Experimental rats were fitted with 3rd ventricle (3V) guide cannula 12 days after Lep-Sap or Blk-Sap injections. Nine days later cannula placement was tested with Angiotensin II and rats were adapted to calorimeter cages for 4 days. Lep-Sap had no effect on body weight. To test leptin responsiveness rats were food deprived for 5 hours and at 5 p.m. they received 3V injections of 0, 0.05, 0.1, 0.25 or 0.5 μg leptin. Food was returned at 6 p.m., the start of the dark period. Each rat received the injections in random order at 4 day intervals. At the end of the experiment NTS pSTAT3 was used to confirm effcacy of Lep-Sap injections. Seven Lep-Sap and 6 control Blk-Sap rats completed the experiment. There was a dose-dependent inhibition of food intake in Blk-Sap rats, but only 0.5 μg leptin inhibited intake of Lep-Sap rats. Intake was inhibited during the 24 hours following injection and was not compensated for so that cumulative intake was inhibited for 60 hours post-injection. Energy expenditure was not different between groups and respiratory exchange ratio tended to follow food intake. These data suggest that leptin- induced inhibition of food intake is mediated by an integrated network involving both the forebrain and hindbrain and that activation of NTS ObRb lowers the threshold for leptin responsiveness in the forebrain.
Related Products: Leptin-SAP (Cat. #IT-47)
Leptin receptor-expressing neurons in ventromedial nucleus of the hypothalamus contribute to weight loss caused by fourth ventricle leptin infusions.
Seamon M, Ahn W, Li AJ, Ritter S, Harris RBS (2019) Leptin receptor-expressing neurons in ventromedial nucleus of the hypothalamus contribute to weight loss caused by fourth ventricle leptin infusions. Am J Physiol Endocrinol Metab 317(4):E586-E596. doi: 10.1152/ajpendo.00205.2019
Objective: To test the importance of VMH leptin responsiveness in mediating weight loss caused by fourth ventricle leptin infusion.
Summary: Leptin did not inhibit food intake and respiratory exchange ratio in rats treated with Leptin-SAP. VMH leptin receptors do not play a significant role in maintaining energy balance in basal conditions, but limit weight gain during positive energy balance.
Usage: Bilateral VMH 75-nl injections of 260 ng/ml of Leptin-SAP or Blank-SAP.
Related Products: Leptin-SAP (Cat. #IT-47), Blank-SAP (Cat. #IT-21)
Circadian aspects of adipokine regulation in rodents
Challet E (2017) Circadian aspects of adipokine regulation in rodents. Best Practice & Research Clinical Endocrinology & Metabolism 31:573-582. doi: 10.1016/j.beem.2017.09.003
Summary: This paper reviews reciprocal links between the circadian clocks and rhythmic secretion of leptin, and discusses the metabolic impact of circadian desynchronization and altered rhythmic leptin. The authors report that leptin is well-known to modulate the timing of food intake by its anorectic effects mostly mediated by the arcuate nuclei of the hypothalamus. They cite a report by Li et al. demonstrating damage to the arcuate neurons expressing leptin receptors by local injections of Leptin-SAP (Cat. #IT-47) leads to hyperphagia coupled to arrhythmic pattern of feeding.
Related Products: Leptin-SAP (Cat. #IT-47)
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Editorial: Circadian Rhythms and Metabolism
Challet E, Kalsbeek A (2017) Editorial: Circadian Rhythms and Metabolism. Front Endocrinol (Lausanne) 8:201. doi: 10.3389/fendo.2017.00201
Related Products: Leptin-SAP (Cat. #IT-47)
Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction.
Wiater MF, Li AJ, Dinh TT, Jansen HT, Ritter S (2013) Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction. Am J Physiol Regul Integr Comp Physiol 305(8):R949-R960. doi: 10.1152/ajpregu.00032.2013
Summary: The arcuate nucleus (Arc) of the hypothalamus is known to participate in the regulation of feeding, adiposity, and leptin-dependent metabolism. The authors examined the role of leptin-receptive neurons in locomotor and temperature rhythms. Rats received four bilateral injections of Leptin-SAP (Cat. #IT-47) into the Arc; Blank-SAP (Cat. #IT-21) was used as a control. The lesion affected learning connected to light cycles, but not learning connected to food schedules, suggesting a mechanism for internal desynchrony that might play a role in obesity and other metabolic disorders.
Related Products: Leptin-SAP (Cat. #IT-47), Blank-SAP (Cat. #IT-21)