Therapies for Treatment-Resistant Childhood Obesity
Testing Novel Pathways for Obesity Drugs
Novel anti-obesity drugs with increased efficacy and safety are urgently needed. The most striking examples of treatment-resistant childhood obesity are observed in patients with dysfunctional hypothalamic signaling, such as in Prader-Willi-Syndrome (PWS), hypothalamic obesity (HO) due to craniopharyngioma, or in subjects with deficient melanocortin signaling, leading to hyperphagia and excessive weight gain. Current genetic PWS rodent models display a limited number of PWS features. Most monogenic causes of obesity are rare and do not represent the vast majority of obese patients, except for melanocortin-4-receptor mutations, that are found in 2-7% of patients with early onset severe obesity.
Dr. Roth has developed an innovative rat model of combined medial hypothalamic lesions that best mimic metabolic changes characteristic of HO and that are related to leptin resistance, melanocortin deficiency, and inflammation. In this model, hyperphagia and postsurgical weight gain are associated with decreased hypothalamic mRNA levels of anorexic peptides, but increased number of microglia and stimulation of the nuclear factor kappa B pathway in the mediobasal hypothalamus. Due to the hypothalamic lesion, this is a model for disturbed hypothalamic signaling but intact hindbrain satiety signaling pathways.
The Roth lab is currently testing potential body weight-reducing agents, including endogenous peptides and their analogs to restore deficient signaling due to disturbed hypothalamic mechanisms. The lab is equipped with a modern caging system to continuously monitor food intake, body weight changes, and changes in body temperature and locomotor activity. For drug delivery, the Roth team has experience in using implanted micro-infusion pumps. This method of treatment administration is less stressful on the animal than tethering or injections, minimizing a significant confounding factor to the data. Currently the Roth lab is testing novel oxytocin and gut hormone analogues and their impact on food intake patterns and body weight reduction in lean and obese rodent models, with and without diabetes.
Dr. Roth is interested in collaborating with industry partners to help test new obesity interventions in both pre-clinical and clinical trial settings. His clinical work is focused on validating obesity drug interventions and behavioral therapies in children with obesity. This work also includes patients with HO. Using structural neuroimaging, changes in the hypothalamus such as gliosis are assessed and by using functional magnetic resonance neuroimaging (fMRI), changes in satiety responses in different brain areas are monitored in response to interventions.
Stage of Development
- Pre-clinical in vivo
- Clinical trial
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Tissue sample access
- Clinical trials
- Reinehr T, Roth CL. The gut sensor as regulator of body weight. Endocrine. 2015 May;49(1):35-50. doi: 10.1007/s12020-014-0518-1.
- Henry KE, Elfers CT, Burke RM, Chepurny OG, Holz GG, Blevins JE, Roth CL, Doyle RP. Vitamin B(12) Conjugation of Peptide-YY(3-36) Decreases Food Intake Compared to Native Peptide-YY(3-36) Upon Subcutaneous Administration in Male Rats. Endocrinology 2015 May;156(5):1739-49. doi: 10.1210/en.2014-1825. Epub 2015 Feb 6. PubMed PMID: 25658456
- Roth CL, Eslamy H, Werny D, Elfers C, Shaffer ML, Pihoker C, Ojemann J, Dobyns WB. Semi-quantitative analysis of hypothalamic damage on MRI predicts risk for hypothalamic Obesity. Obesity (Silver Spring). 2015 Jun;23(6):1226-33. doi: 10.1002/oby.21067
- Roth, CL. Hypothalamic obesity: Disturbed energy homeostasis related to hypothalamic damage and potential interventions. J Clin Med 2015, 4(9), 1774-1797; doi:10.3390/jcm4091774
- Henry KE, Kerwood DJ, Allis DG, Workinger JL, Bonaccorso RL, Holz GG, Roth CL, Zubieta J, Doyle RP. Solution Structure and Constrained Molecular Dynamics Study of Vitamin B12 Conjugates of the Anorectic Peptide PYY(3-36). ChemMedChem. 2016 May 6;11(9):1015-21. doi: 10.1002/cmdc.201600073. Epub 2016 Mar 30. PubMed PMID: 27027248; PubMed Central PMCID: PMC4878914.
- Roth CL, D'Ambrosio G, Elfers C. Activation of nuclear factor kappa B pathway and reduction of hypothalamic oxytocin following hypothalamic lesions. J Syst Integr Neurosci. 2016 Feb;2(1):79-84. Epub 2016 Jan 29. PubMed PMID: 27512604; PubMed Central PMCID: PMC4976786
- Enriori PJ, Chen W, Garcia-Rudaz MC, Grayson BE, Evans AE...Roth CL, Grove KL, Cowley MA. α-Melanocyte stimulating hormone promotes muscle glucose uptake via melanocortin 5 receptors. Mol Metab. 2016 Aug 5;5(10):807-22. doi: 10.1016/j.molmet.2016.07.009. eCollection 2016 Oct. PubMed PMID: 27688995.
- Elfers CT, Roth CL. Robust reductions of excess weight and hyperphagia by beloranib in rat models of genetic and hypothalamic obesity. Endocrinology. 2017;158(1):41-55. doi: 10.1210/en.2016-1665. PMID: 27849360
- Roth CL, Elfers C, Hampe CS. Assessment of disturbed glucose metabolism and surrogate measures of insulin sensitivity in obese children and adolescents. Nutr Diabetes. 2017 Dec 14;7(12):301. doi: 10.1038/s41387-017-0004-y. PubMed PMID:29242622.
- Chepurny OG, Bonaccorso RL, Leech CA, Wöllert T, Langford GM, Schwede F, Roth CL, Doyle RP, Holz GG. Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. Sci Rep. 2018 Feb 28;8(1):3749. doi: 10.1038/s41598-018-22106-1. Erratum in: Sci Rep. 2018 Apr 13;8(1):6192. PubMed PMID: 29491394; PubMed Central PMCID: PMC5830615.
- Roth CL, Melhorn SJ, Elfers CT, Scholz K, De Leon MRB, Rowland M, Kearns S, Aylward E, Grabowski TJ, Saelens BE, Schur EA. Central Nervous System and Peripheral Hormone Responses to a Meal in Children. J Clin Endocrinol Metab. 2019 May 1;104(5):1471-1483. doi: 10.1210/jc.2018-01525.
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