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.

Research focus

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

  • Valencia-Torres, L., Olarte-Sanchez, CM., Lyons, DJ., Georgescu, T., Greewald-Yarnell, M., Myers, MG., Bradshaw, CM. & Heisler, LK. (2017). 'Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation'. Neuropsychopharmacology, vol 42, no. 7, pp. 1511-1521.
    [Online] DOI: 10.1038/npp.2016.264
    [Online] AURA: npp2016264a.pdf
  • Xu, P., He, Y., Cao, X., Valencia-Torres, L., Yan, X., Saito, K., Wang, C., Yang, Y., Hinton Jr., A., Zhu, L., Shu, G., Myers Jr., MG., Wu, Q., Tong, Q., Heisler, LK. & Xu, Y. (2017). 'Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice'. Biological Psychiatry, vol 81, no. 9, pp. 737-747.
    [Online] DOI: 10.1016/j.biopsych.2016.06.005
    [Online] AURA: 1_s2.0_S0006322316324702_main.pdf
  • Garfield, AS., Davies, JR., Burke, LK., Furby, HV., Wilkinson, LS., Heisler, LK. & Isles, AR. (2016). 'Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite'. Molecular brain, vol 9, no. 1, 95.
    [Online] DOI: 10.1186/s13041-016-0277-4
    [Online] AURA: Increased_alternate_splicing_of_Htr2c_in_a_mouse_model_for_P...
  • Markkula, SP., Lyons, D., Yueh, C-Y, Riches, C., Hurst, P., Fielding, B., Heisler, LK. & Evans, ML. (2016). 'Intracerebroventricular Catalase Reduces Hepatic Insulin Sensitivity and Increases Responses to Hypoglycemia in Rats'. Endocrinology, vol 157, no. 12, pp. 4669–4676.
    [Online] DOI: 10.1210/en.2015-2054
    [Online] AURA: en_2E2015_2054.pdf
  • Marcinkiewcz, CA., Mazzone, CM., D'Agostino, G., Halladay, LR., Hardaway, JA., DiBerto, JF., Navarro, M., Burnham, N., Cristiano, C., Dorrier, CE., Tipton, GJ., Ramakrishnan, C., Kozicz, T., Deisseroth, K., Thiele, TE., McElligott, ZA., Holmes, A., Heisler, LK. & Kash, TL. (2016). 'Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala'. Nature, vol 537, 19318, pp. 97-101.
    [Online] DOI: 10.1038/nature19318
    [Online] AURA: Tom_27sNATURE_4_merged_1469007630.pdf
  • Yavari, A., Stocker, CJ., Ghaffari, S., Wargent, ET., Steeples, V., Czibik, G., Pinter, K., Bellahcene, M., Woods, A., Martínez de Morentin, PB., Cansell, C., Lam, BYH., Chuster, A., Petkevicius, K., Nguyen-Tu, M-S, Martinez-Sanchez, A., Pullen, TJ., Oliver, PL., Stockenhuber, A., Nguyen, C., Lazdam, M., O'Dowd, JF., Harikumar, P., Tóth, M., Beall, C., Kyriakou, T., Parnis, J., Sarma, D., Katritsis, G., Wortmann, DDJ., Harper, AR., Brown, LA., Willows, R., Gandra, S., Poncio, V., de Oliveira Figueiredo, MJ., Qi, NR., Peirson, SN., McCrimmon, RJ., Gereben, B., Tretter, L., Fekete, C., Redwood, C., Yeo, GSH., Heisler, LK., Rutter, GA., Smith, MA., Withers, DJ., Carling, D., Sternick, EB., Arch, JRS., Cawthorne, MA., Watkins, H. & Ashrafian, H. (2016). 'Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function'. Cell Metabolism, vol 23, no. 5, pp. 821-836.
    [Online] DOI: 10.1016/j.cmet.2016.04.003
    [Online] AURA: 1_s2.0_S1550413116301231_main.pdf