Energy metabolism is tightly regulated, and disruptions in the metabolic homeostasis could lead to metabolic syndromes such as obesity and type II diabetes. Inflammation is a prominent disrupter of energy metabolism. Thus, understanding molecular pathways of inflammation-induced metabolic disorders is critical to combat metabolic diseases. Inflammatory signaling molecules such as c-Jun N-terminal kinase (JNK) and NF-?B have been identified as mediators of metabolic diseases. JNK and NF-?B inhibit insulin receptor substrate 1, which is responsible for insulin resistance in several tissue including liver and adipose tissues. In addition to the JNK- and NF-?B-dependent mechanisms, emerging evidence indicates that endoplasmic reticulum (ER) stress is the major pathway linking inflammation and metabolic disorders. However, the molecular mechanism by which inflammation induces ER stress is not yet clear. We found that deletion of a protein kinase TAK1 protects cells from ER stress, and that neuron-specific TAK1 deletion blocks inflammation associated metabolic disorders including excess weight gain. TAK1 belongs to the mitogen-activated protein kinase kinase kinase (MAP3K) family, and is an intermediate of inflammatory signaling pathways. TAK1 can activate JNK and NF-?B; however, activity of JNK and NF-?B is unaltered in the deletion of Tak1 in neurons. Thus, TAK1 modulates ER stress and energy metabolism through a previously uncharacterized pathway. In an effort to determine a new downstream pathway of TAK1, we have found that TAK1 inhibits a transcription factor SREBP, which is the key regulator of lipogenesis. Lipogenesis is important for membrane biogenesis and its alteration impacts the ER mass and function. We hypothesize that inflammation-induced TAK1 activation downregulates membrane biogenesis through inhibiting SREBP-dependent lipogenesis, which is causally associated with ER stress and the disorder in neuronal regulation of systemic energy metabolism. In this project, we will delineate: 1) the molecular mechanism by which TAK1 modulates lipogenesis, 2) the role of TAK1-lipogenesis pathway in ER stress, and 3) the link between neuronal TAK1-lipogenesis-ER stress pathway and systemic metabolic disorders. Outcomes of this project will reveal a new mechanistic link between inflammation and energy metabolism.

Public Health Relevance

Metabolic diseases including type II diabetes and obesity are closely associated with inflammation; however, our understanding of the molecular mechanisms through which inflammation disrupts metabolism is still limited. We have found that a protein kinase called TAK1 is critically involved in inflammation-induced obesity through a previously unknown mechanism. In this project, we will delineate this TAK1-dependent metabolic disruption, which will uncover new molecules and pathways in regulation of energy metabolism and could provide new therapeutic targets to block inflammation-induced metabolic diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Marino, Pamela
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
North Carolina State University Raleigh
Schools of Arts and Sciences
United States
Zip Code
Sakamachi, Yosuke; Morioka, Sho; Mihaly, September R et al. (2017) TAK1 regulates resident macrophages by protecting lysosomal integrity. Cell Death Dis 8:e2598
Mihaly, September R; Sakamachi, Yosuke; Ninomiya-Tsuji, Jun et al. (2017) Noncanocial cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGF?-activated kinase 1. Sci Rep 7:2918
Sai, Kazuhito; Morioka, Sho; Takaesu, Giichi et al. (2016) TAK1 determines susceptibility to endoplasmic reticulum stress and leptin resistance in the hypothalamus. J Cell Sci 129:1855-65
Morioka, S; Sai, K; Omori, E et al. (2016) TAK1 regulates hepatic lipid homeostasis through SREBP. Oncogene 35:3829-38
Simmons, A N; Kajino-Sakamoto, R; Ninomiya-Tsuji, J (2016) TAK1 regulates Paneth cell integrity partly through blocking necroptosis. Cell Death Dis 7:e2196
Hashimoto, Kazunori; Simmons, Alicia N; Kajino-Sakamoto, Rie et al. (2016) TAK1 Regulates the Nrf2 Antioxidant System Through Modulating p62/SQSTM1. Antioxid Redox Signal 25:953-964