Michael Wolfgang
Assistant Professor of Biological Chemistry
Johns Hopkins University School of Medicine

Our laboratory is interested in the regulation of energy homeostasis by the central nervous system (CNS). Specifically, we are interested in the reciprocal interaction between the CNS and peripheral metabolic tissues (e.g. liver, muscle and adipose) that mediate energy homeostasis.  This interaction is often disrupted in obese and diabetic patients leading to the inability to properly regulate body weight and blood glucose within physiological norms. Obesity and diabetes have become serious problems in Western medical science, and are a growing problem throughout the world.  Understanding the molecular mechanisms underpinning these conditions is critical to formulating new interventions.  To this end we utilize biochemical and molecular genetic techniques to understand the molecular mechanisms that the CNS uses to signal energy homeostasis.

We are interested in exploring two functionally similar yet mechanistically distinct signaling paradigms:

1) Cytokine/Endocrine signaling.  Cytokines such as leptin have profound effects on energy homeostasis, and some mediate the majority of their effect on peripheral metabolism through the central nervous system.  For example, administration of leptin to the CNS of leptin deficient or lipodystrophic mice leads to a decrease in food intake, but also mediates changes in gene expression in the liver and vastly improved insulin sensitivity throughout the body that proceeds changes in body weight.  We are interested in elucidating the neural signaling pathways that mediate these changes. 

Questions:
1) How do cytokines that effect energy homeostasis signal in the brain? 
2) What neural circuits are involved?
3) How does the CNS interact with the periphery?

2) Nutrient sensing.  Circulating nutrients such as fatty acids, glucose and amino acids have been shown to signal via the CNS to effect body weight and present new signaling paradigms for body weight regulation by the CNS.  Previously, we have worked on the effect of fatty acid intermediates and glucose on the brain’s ability to regulate energy homeostasis.  Recently, we have been studying the role of a novel, brain-specific enzyme, carnitine palmitoyltransferase-1c (CPT1c). CPT1c KO mice have unique metabolic characteristics and CPT1c has enigmatic biochemical properties.  We are interested in elucidating how nutrients effect neural responses to hungry and satiety.

Questions:
1) What is the CPT1c enzymatic reaction and physiologic function?
2) What are the roles of metabolic intermediates in neural signal transduction?
3) What is the role of fatty acid catabolism in the CNS?
4) How do endocrine and nutritional inputs interact?

Kano A*, Wolfgang MJ*, Gao Q*, Jacoby J, Chai GX, Hansen W, Iwamoto Y, Pober JS, Flavell RA, & Fu XY.  Endothelial cells require STAT3 for protection against endotoxin-induced inflammation.  J Exp Med.  2003; 198(10): 1517-1525. (*equal contribution)

Gao Q*, Wolfgang MJ*, Neschen S, Morino K, Horvath, TL, Shulman GI, & Fu XY.  Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility and thermal dysregulation.  Proc. Natl. Acad. Sci. USA 2004 March; 101(13): 4661-4666. (*equal contribution)

Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto S, Cha SH, Shimokawa T & Lane MD.  The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc. Natl. Acad. Sci. USA 2006 May; 103(19): 7282-7287.

Wolfgang MJ & Lane MD. Control of Energy Homeostasis:  role of enzymes and intermediates of fatty acid metabolism in the central nervous system.  Annu Rev Nutr. 2006; 26:23-44.

Wolfgang MJ & Lane MD. The role of hypothalamic malonyl-CoA in energy homeostasis. J. Biol. Chem. 2006; 281(49): 37265-37269.

Chakravarthy MV, Zhu Y, López M, Yin L,  Wozniak DF, Coleman T, Hu Z, Wolfgang M, Vidal-Puig A,  Lane MD & Semenkovich CF. Brain fatty acid synthase activates PPARa to maintain energy homeostasis.  J Clin Invest. 2007; 117: 2539-2552.

Wolfgang MJ, Cha SH, Sidhaye A, Chohnan S, Cline G, Shulman GI & Lane MD. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc Natl Acad Sci USA. 2007 Dec; 104(49): 19285-19290.

Wolfgang MJ, Cha SH, Millington DS, Cline G, Shulman GI, Suwa A, Asaumi M, Kurama T, Shimokawa, T & Lane MD. Brain-specific carnitine palmitoyltransferase-1c:  Role in CNS fatty acid metabolism, food intake and body weight. J Neurochem 2008; May;105(4):1550-9.