Central and peripheral mechanisms regulating energy and glucose homeostasis
Author: Zachariah Tom, Robby
Date: 2013-06-13
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna.
Time: 13.00
Department: Inst för molekylär medicin och kirurgi / Dept of Molecular Medicine and Surgery
Abstract
Obesity is a major health concern across the globe and is often associated with insulin resistance and type 2 diabetes. The coupling of ene rgy intake and expenditure is tightly regulated by central and peripheral mechanisms and is dysregulated in obesity. This thesis focuses on the role of central and peripheral mechanisms regulated by signaling via the leptin receptor and AMP2-activated protein kinase (AMPK) in regulating energy and glucose homeostasis.
Leptin signaling through the long form of the leptin receptor (LepRb) plays a role in the regulation of glucose and energy homeostasis. Leptin action is mediated by phosphorylation of several tyrosine residues on LepRb, of which Tyr985 plays a major role. The aim of Study I was to elucidate the role of LepRb2Tyr985 in glucose metabolism. LepRb2Tyr985 mutant mice (l/l mice) that lack feedback inhibition of LepRb signaling had improved glucose tolerance and insulin sensitivity. Euglycemic2 hyperinsulinemic clamp studies performed in l/l mice revealed enhanced hepatic and peripheral insulin sensitivity. Thus, LepRb2Tyr9852 mediated signals regulate whole2 body glucose metabolism and insulin sensitivity.
Tissue-specific alterations in mitochondrial respir ation have been implicated in obesity and type 2 diabetes. The aim of Study II was to determine the role of leptin in regulating tissue-specific mitochondrial respiratio n in obese leptin-deficient ob/ob mice. Hepatic mitochondrial respiration was reduced in ob/ob mice and unaltered by short-term leptin treatment. Mitochondrial electron transport capacity was enhanced in glycolytic extensor digitorum longus (EDL) muscle, whereas mitochondrial function in oxidative soleus muscle was unaltered by obesity or leptin treatment in ob/ob mice. The present study highlights the tissue-specific mitoch ondrial adaptations imposed by obesity and its modulation by short-term leptin treatment.
AMPK is activated in response to cellular energy demand and turns on cellular processes that restore energy balance. Skeletal muscle overexpression of an activating form of AMPK (AMPKγ3R225Q) provides protection from high-fat diet induced insulin resistance. Study III was designed to test the hypothesis that skeletal muscle-specific expression of the AMPKγ3R225Q isoform rescues the metabolic abnormalities associated with leptin deficiency in ob/ob mice (ob/ob 2γ3R225Q). The AMPKγ3R225Q mutation confers favorable metabolic adaptations including increased skeletal muscle glycogen content and decreased intramuscular triglyceride content, but glucose tolerance and skeletal muscle insulin-stimulated glucose uptake was unaltered. This implies that central defects arising from leptin deficiency over rides many of the positive benefits brought about by peripheral AMPK signaling.
Collectively, the results presented in this thesis highlight the role of leptin receptor and AMPK signaling in the regulation of glucose and lipid metabolism from a whole-body perspective. Strategies targeted at improving leptin sensitivity and skeletal muscle-specific AMPK activation open up new venues for the treatment of metabolic complications associated with diabetes and obesity.
Leptin signaling through the long form of the leptin receptor (LepRb) plays a role in the regulation of glucose and energy homeostasis. Leptin action is mediated by phosphorylation of several tyrosine residues on LepRb, of which Tyr985 plays a major role. The aim of Study I was to elucidate the role of LepRb2Tyr985 in glucose metabolism. LepRb2Tyr985 mutant mice (l/l mice) that lack feedback inhibition of LepRb signaling had improved glucose tolerance and insulin sensitivity. Euglycemic2 hyperinsulinemic clamp studies performed in l/l mice revealed enhanced hepatic and peripheral insulin sensitivity. Thus, LepRb2Tyr9852 mediated signals regulate whole2 body glucose metabolism and insulin sensitivity.
Tissue-specific alterations in mitochondrial respir ation have been implicated in obesity and type 2 diabetes. The aim of Study II was to determine the role of leptin in regulating tissue-specific mitochondrial respiratio n in obese leptin-deficient ob/ob mice. Hepatic mitochondrial respiration was reduced in ob/ob mice and unaltered by short-term leptin treatment. Mitochondrial electron transport capacity was enhanced in glycolytic extensor digitorum longus (EDL) muscle, whereas mitochondrial function in oxidative soleus muscle was unaltered by obesity or leptin treatment in ob/ob mice. The present study highlights the tissue-specific mitoch ondrial adaptations imposed by obesity and its modulation by short-term leptin treatment.
AMPK is activated in response to cellular energy demand and turns on cellular processes that restore energy balance. Skeletal muscle overexpression of an activating form of AMPK (AMPKγ3R225Q) provides protection from high-fat diet induced insulin resistance. Study III was designed to test the hypothesis that skeletal muscle-specific expression of the AMPKγ3R225Q isoform rescues the metabolic abnormalities associated with leptin deficiency in ob/ob mice (ob/ob 2γ3R225Q). The AMPKγ3R225Q mutation confers favorable metabolic adaptations including increased skeletal muscle glycogen content and decreased intramuscular triglyceride content, but glucose tolerance and skeletal muscle insulin-stimulated glucose uptake was unaltered. This implies that central defects arising from leptin deficiency over rides many of the positive benefits brought about by peripheral AMPK signaling.
Collectively, the results presented in this thesis highlight the role of leptin receptor and AMPK signaling in the regulation of glucose and lipid metabolism from a whole-body perspective. Strategies targeted at improving leptin sensitivity and skeletal muscle-specific AMPK activation open up new venues for the treatment of metabolic complications associated with diabetes and obesity.
List of papers:
I. Tom RZ, Sjögren RJ, Vieira E, Glund S, Iglesias-Gutiérrez E, Garcia-Roves PM, Myers MG Jr., Björnholm M. Increased hepatic insulin sensitivity in mice lacking inhibitory leptin receptor signals. Endocrinology. 152(6):2237246, 2011.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Holmström MH, Tom RZ, Björnholm M, Garcia-Roves PM, Zierath JR. Effect of leptin treatment on mitochondrial function in obese leptin-deficient ob/ob mice. Metabolism. 2013.
Fulltext (DOI)
Pubmed
III. Tom RZ, Garcia Roves PM, Sjögren RJ, Jiang LQ, Holmström MH, Deshmukh AS, Vieira E, Björnholm M, Zierath JR. Effects of AMPK activation on insulin sensitivity a nd metabolism in leptin-deficient ob/ob mice. [Accepted]
Fulltext (DOI)
Pubmed
I. Tom RZ, Sjögren RJ, Vieira E, Glund S, Iglesias-Gutiérrez E, Garcia-Roves PM, Myers MG Jr., Björnholm M. Increased hepatic insulin sensitivity in mice lacking inhibitory leptin receptor signals. Endocrinology. 152(6):2237246, 2011.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Holmström MH, Tom RZ, Björnholm M, Garcia-Roves PM, Zierath JR. Effect of leptin treatment on mitochondrial function in obese leptin-deficient ob/ob mice. Metabolism. 2013.
Fulltext (DOI)
Pubmed
III. Tom RZ, Garcia Roves PM, Sjögren RJ, Jiang LQ, Holmström MH, Deshmukh AS, Vieira E, Björnholm M, Zierath JR. Effects of AMPK activation on insulin sensitivity a nd metabolism in leptin-deficient ob/ob mice. [Accepted]
Fulltext (DOI)
Pubmed
Institution: Karolinska Institutet
Supervisor: Björnholm, Marie
Issue date: 2013-05-23
Rights:
Publication year: 2013
ISBN: 978-91-7549-204-9
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