The primary focus of the Flak lab is to study the neural circuits relevant to obesity and diabetes, particularly the neural mechanisms that underlie the control of energy expenditure and glucose homeostasis. The current goals of the flak lab are to reveal the downstream mechanism engaged for separate cells that control these two functions intermingled within the same nucleus, how pharmaceutical obesity strategies engage this circuit, and how cancer activates these circuits. The Flak lab uses a combination of molecular biology, neuroanatomy, and pharmacological approaches in knock-in mouse models to selective study the mechanisms of individual cells, receptors, or transmitters within separate nodes along the circuit.
Glucose Homeostasis and the Brain
It is well understood that the brain can control energy balance via descending connections (i.e., sympathetic nervous system) with peripheral organs (e.g., pancreas, heart, liver, adrenal). However, the details of these brain systems have not yet been established. While therapies exist that can successfully target the sympathetic nervous system to restore normal function in obese and diabetic patients, these tools also produce deleterious effects on unwanted and unrelated processes (e.g., cardiovascular disease, renal failure). Thus, the upstream neural system that can specifically target, for example, glucose mobilization, represents the ideal target to curb medical issues associated with complications such as hypoglycemia. Yet, there is only a superficial understanding of the unique cellular components contained within the neural circuits that control these processes. The Flak Lab is investigating how the brain can separately initiate glucose mobilization and glucose uptake when necessary, with the help of the ADA Pathway Program. The Flak Lab’s goal is to identify ways to target these circuits to promote glucose mobilization during hypoglycemia or curb diabetic hyperglycemia.
Energy Expenditure and the Brain
In addition to the control of glucose, many overlapping components in these brain areas that influence glucose homeostasis also can influence energy expenditure. Concurrently, the Flak Lab also aims to understand the circuits in the brain that separately control energy expenditure, especially those circuits that can be promoted during periods of exercise and suppressed during fasting and diet conditions. These circuits likely engage signaling within adipose tissue and muscle that facilitate energy metabolism. It has long been known that norepinephrine is a key signal in driving these responses, but it is not clear how the brain participates in this function. The Flak lab’s goal is to identify unique neural pathways that can stimulate peripheral energy metabolism targeted to the adipose tissue and muscle, without the widespread side effects of sympathetic agonists. In addition to uncovering the underlying pathway, the Flak lab is also identifying signals (e.g. future potential pharmaceutical targets and physiologic states) that act via these systems to control energy balance. This includes how dieting may inhibit parts of this pathway and cancer may activate parts of this pathway.
Current Research Funding
(PI) Ralph W. and Grace M. Showalter Award, Identifying novel CNS mechanisms that stimulate energy expenditure, PI: Jonathan N. Flak, 5% effort, 7/2022-6/2023, $75,000
(PI) Lilly Research Award Program, Energy expenditure engagement by multi-receptor agonists via the CNS, PI: Jonathan N. Flak, 5% effort, 2/2021-1/2023, $264,000
(PI) American Diabetes Association Pathway Initiator Award, 17-INI-15, Targeting the VMN to understand hypoglycemia pathogenesis, PI: Jonathan N. Flak, 50% effort, 1/2017-12/2023, $1,625,000
Recent Publications
Flak J.N., Patterson C.M., Garfield A.S., D’Agostino G., Goforth P.B., Sutton A.K., Malec P.A., Wong J.M., Germani M., Jones J.C., Rajala M., Satin L., Rhodes C.J., Olson D.P., Kennedy R.T., Heisler L.K., Myers M.G. Jr. Leptin-Inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nature Neuroscience (2014); 17 (12): 1744-50.
Flak J.N., Myers M.G. Jr. CNS Mechanisms of Leptin Action. Mol. Endocrinology (2016); 30 (1): 3-12.
Flak J.N., Arble D., Pan W., Patterson C.M., Lanigan T., Sacksner J., Joosten M., Morgan D., Allison M.B., Hayes J., Feldman E., Seeley R.J., Olson D.P., Rahmouni K., Myers M.G. Jr. A leptin-regulated neural circuit that modulates glucose mobilization in response to noxious stimuli. Journal of Clinical Investigation (2017); 127(8): 3103-3113.
Flak J.N., Goforth P.B., Dell’Orco J., Sabatini P.V., Li C., Bozadjieva N., Sorenson M., Valenta A., Cras-Meneur C., Ansari A., Sacksner J., Kodur N., Sandoval D., Kennedy R.T., Olson D.P., Myers M.G. Jr. Ventromedial hypothalamic nucleus CCKBR neurons mediate the insulin-independent homeostatic and allostatic control of blood glucose. Journal of Clinical Investigation (2020); 130 (6): 2943-2952.
Bozadjieva-Kramer N., Ross R.A., Johnson D.Q., Fenseleau H., Haggerty D.L., Atwood B., Lowell B.B., Flak J.N. The role of mediobasal hypothalamic PACAP in the control of body weight and metabolism. Endocrinology (2021); 162(4): 1-15.
