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Principal Investigator: Congcong He
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $384,000
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract
The goal of this proposal is to demonstrate a novel non-degradative, non-cell autonomous, mechanism
by which the autophagy machinery regulates metabolism. Although emerging evidence suggests that autophagy
abnormality is implicated in metabolic dysfunction, the mechanism by which autophagy regulates insulin
sensitivity is largely unknown. Autophagy is generally considered as a destruction and degradation process via
lysosomes. We recently discovered a new non-degradative function regulated by a ULK1-Vps34-Becn1
autophagy machinery in adipose tissue, which may play a pivotal role in systemic AMPK activation and insulin
sensitization. Adiponectin is an adipose-derived hormone (adipokine), whose reduction in circulation is strongly
associated with type 2 diabetes (T2D) and metabolic syndrome. Hypoadiponectinemia caused by SNPs or
mutations in the Adiponectin gene in humans has been associated with insulin resistance and T2D, and
adiponectin knockout mice phenocopy the human phenotypes and develop insulin resistance. However, despite
the functional importance of adiponectin, the mechanism that regulates adiponectin secretion has received little
research attention and remains obscure. We found that autophagy-hyperactive mutant mice harboring an active
mutation in the essential autophagy protein Becn1 (Becn1F121A knock-in mice) have improved insulin sensitivity
in response to high-fat diet feeding, which is caused by factors in the circulation. To identify the Becn1-regulated,
insulin-sensitizing, circulating factors, we performed a hormonal screen and identified a higher level of
adiponectin in the serum of autophagy-hyperactive Becn1F121A mice. We found that on one hand, adipose-
specific Becn1F121A expression is sufficient to improve systemic insulin sensitivity and increase circulating
adiponectin levels; on the other hand, depleting Becn1, or inhibiting two upstream autophagy kinases, ULK1 and
Vps34, reduces circulating adiponectin in mice. Using proteomic and biochemical approaches, we discovered
that the exocyst component Sec6/Exoc3 is a binding partner of Becn1, and preferentially binds to the hyperactive
form, Becn1F121A. Motivated by the preliminary data, we propose our overall hypothesis that a ULK1-Vps34-
Becn1 autophagy axis improves insulin sensitivity by promoting adiponectin secretion via Becn1-exocyst binding
in adipocytes. We term this pathway as “autophagy-facilitated secretion”. To test the hypothesis, we propose the
following aims, using a combination of genetic, imaging, cell biology, biochemistry, and metabolic approaches:
Aim 1 is to determine whether active Becn1 activates AMPK and improves insulin sensitivity via adiponectin
signaling; Aim 2 is to determine whether a ULK1-Vps34-Becn1 autophagy axis functions in adipose tissue to
non-cell autonomously regulate systemic insulin sensitivity; and Aim 3 is to demonstrate the molecular
mechanism by which the Becn1-centered autophagy machinery regulates adiponectin secretion via the crosstalk
with the exocyst pathway. Overall, our study will establish a new mechanistic paradigm for the Becn1-centered
autophagy pathway in adipose tissue to prevent T2D, beyond its role in self-degradation.
Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><5'-AMP-activated protein kinase><ACRP30 protein><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Attention><Autophagocytosis><Autophagosome><Autoregulation><Binding><Biochemical><Biochemistry><Biological Chemistry><Blood Serum><Body Tissues><Cell Communication and Signaling><Cell Signaling><Cellular biology><Circulation><Complex><Data><Endocrine Gland Secretion><Endocrine Glands><Endocrine Organs><Endoplasmic Reticulum><Ergastoplasm><Fat Cells><Fatty Tissue><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><High Fat Diet><Homeostasis><Hormonal><Hormones><Human><Humulin R><Hyperactivity><Image><Insulin><Insulin Resistance><Intermediary Metabolism><Intracellular Communication and Signaling><KI mice><KO mice><Ketosis-Resistant Diabetes Mellitus><Kinases><Knock-in Mouse><Knock-out Mice><Knockout Mice><Link><Lipocytes><LoxP-flanked allele><Lysosomes><Maintenance><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Metabolic><Metabolic Processes><Metabolic dysfunction><Metabolic syndrome><Metabolism><Mice><Mice Mammals><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Mutant Strains Mice><Mutation><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Null Mouse><Pathway interactions><Phenocopy><Phenotype><Phosphotransferase Gene><Phosphotransferases><Physiological Homeostasis><Play><Process><Proteins><Proteomics><Receptor Signaling><Regular Insulin><Regulation><Research><Role><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><System><T2 DM><T2D><T2DM><Testing><Therapeutic Hormone><Tissues><Transphosphorylases><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vesicle><adipocyte complement-related protein 30-kDa><adipocyte, C1q and collagen domain containing protein><adipocytokines><adipokines><adiponectin><adipose><adult onset diabetes><apM-1 protein><apM1 (adipose-specific) protein><autophagy><biological signal transduction><cell biology><feeding><floxed><floxed allele><genome mutation><glucose tolerance><hydroxymethylglutaryl-CoA-reductase kinase><imaging><improved><insulin resistant><insulin sensitivity><insulin tolerance><ketosis resistant diabetes><knockin mice><maturity onset diabetes><mouse model><mouse mutant><murine model><novel><pathway><pharmacologic><prevent><preventing><response><social role><tool><type 2 DM><type II DM><type two diabetes><white adipose tissue><yellow adipose tissue>