Professor Lora Heisler

Professor Lora Heisler

Professor Lora Heisler

Mechanisms underlying the pathophysiology of obesity and type 2 diabetes

The brain represents the master coordinator of appetite and energy expenditure, employing interwoven neurological circuits to continually appraise and respond to changes in energy state.

Our research aims to discover and characterise these brain circuits using cutting edge technology with the objective of locating points within the pathway that are amenable to manipulation with manmade (drug) or natural (hormone) substances.

We also examine the impact of diet and body weight on circuit rewiring and mechanisms restore appropriate system connectivity and activity.

The ultimate aim of our research is to identify new treatments for obesity and type 2 diabetes.

dietWe aim to elucidate the neuroendocrinology of energy homeostasis and neural influences on peripheral metabolism, in order to define novel therapeutic targets for obesity and type 2 diabetes.

There is significant genetic and pharmacological evidence that central melanocortin pathways, mostly through melanocortin-4 receptors, are critical in the regulation of neuroendocrine and behavioural parameters associated with energy balance/type 2 diabetes.

However, relatively little is known about the downstream pathways involved. We are adopting complementary neuroanatomical, pharmacological, genetic, physiological, and behavioural approaches to investigate such brain circuitry.

Specifically, our data suggest that the central serotonin system modulates melanocortin pathways, and we are currently exploring the expression of different serotonin receptors on melanocortin-containing cell bodies, and their differential modulation of effects on key nuclei in the hypothalamus and brainstem.

Research team

D'Agostino G, Lyons DJ, Cristiano C, Burke LK, Madara JC, Campbell JN, Garcia AP, Land BB, Lowell BB, Dileone RJ, Heisler LK. Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. Elife. 2016 Mar 14;5. pii: e12225. doi: 10.7554/eLife.12225. PubMed PMID:26974347; PubMed Central PMCID: PMC4861598.

Yavari A, Stocker CJ, Ghaffari S, Wargent ET, Steeples V, Czibik G, Pinter K, Bellahcene M, Woods A, Martínez de Morentin PB, Cansell C, ….Yeo GS, Heisler LK,Rutter GA, Smith MA, Withers DJ, Carling D, Sternick EB, Arch JR, Cawthorne MA, Watkins H, Ashrafian H. Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function. Cell Metab. 2016 May 10;23(5):821-36. doi: 10.1016/j.cmet.2016.04.003. Epub 2016 Apr 28. PubMed PMID: 27133129; PubMed Central PMCID: PMC4873618.

Martin-Gronert MS, Stocker CJ, Wargent ET, Cripps RL, Garfield AS, Jovanovic Z, D'Agostino G, Yeo GS, Cawthorne MA, Arch JR, Heisler LK, Ozanne SE. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male
rats. Dis Model Mech. 2016 Apr 1;9(4):401-12. doi: 10.1242/dmm.023903. Epub 2016 Jan 14. PubMed PMID: 26769798; PubMed Central PMCID: PMC4852506.Martin-Gronert MS, Stocker CJ, Wargent ET, Cripps RL, Garfield AS, Jovanovic Z, D'Agostino G, Yeo GS,

Cawthorne MA, Arch JR, Heisler LK, Ozanne SE. 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. Dis Model Mech. 2016 Jan 14. [Epub ahead of print]

D'Agostino G, Cristiano C, Lyons DJ, Citraro R, Russo E, Avagliano C, Russo R, Raso GM, Meli R, De Sarro G, Heisler LK, Calignano A. Peroxisome proliferator-activated receptor alpha plays a crucial role in behavioral repetition and cognitive flexibility in mice. Mol Metab. 2015 May 2;4(7):528-36.

Garfield AS, Shah BP, Madara JC, Burke LK, Patterson CM, Flak J, Neve RL, Evans ML, Lowell BB, Myers MG Jr, Heisler LK.  A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia.  Cell Metabolism, 2014; 20(6):1030-7.

Flak JN, Patterson CM, Garfield AS, D'Agostino G, Goforth PB, Sutton AK, Malec PA, Wong JM, Germani M, Jones JC, Rajala M, Satin L, Rhodes CJ, Olson DP, Kennedy RT, Heisler LK, Myers MG Jr.  Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance.  Nature Neuroscience, 2014; 17(12):1744-50.

Burke LK, Doslikova B, D'Agostino G, Garfield AS, Farooq G, Burdakov D, Low MJ, Rubinstein M, Evans ML, Billups B, Heisler LK.  5-HT obesity medication efficacy via POMC activation is maintained during aging.  Endocrinology, 2014; 155(10):3732-8.

Cowley M, Garfield AS, Madon-Simon M, Charalambous M, Clarkson RW, Smalley MJ, Kendrick H, Isles AR, Parry AJ, Carney S, Oakey RJ, Heisler LK, Moorwood K, Wolf JB, Ward A.  Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup.  PLoS Biology, 2014; 12(2):e1001799.

Stanley S, Domingos AI, Kelly L, Garfield A, Damanpour S, Heisler L, Friedman J.  Profiling of Glucose-Sensing Neurons Reveals that GHRH Neurons Are Activated by Hypoglycemia.  Cell Metabolism 2013; 18(4):596-607.