Molecular regulation of skeletal muscle thermogenesis

Project: Research project

Project Details

Description

Abstract The induction of obesity results from an increase in energy storage relative to energy expenditure and until a new energy equilibrium is established at higher pathophysiologic weight. Obesity is increasing at an alarming rate in the USA with approximately one-third of adults and one-fifth of children classified as obese. In addition, to the direct health care costs, work loss and morbidly, obesity is the primary factor driving insulin resistance and type 2 diabetes. At the experimental level over the past decade there has been a substantial effort focused on increasing energy expenditure through the development/activation of brown/beige adipose tissue thermogenesis. In contrast to adipose tissue, collectively skeletal muscle accounts for approximately 50% of body mass, is the primary determinant of basal metabolic rate and is the major driver of increased energy expenditure that occurs during physical activity. In addition, involuntary skeletal muscle contractions or voluntary activity based skeletal muscle contractions accounts for the majority of heat production during cold induced thermogenesis that can reach 15-20 times the resting basal metabolic rate. During our phenotypic characterization of the TIGAR knockout mice, to our surprise these mice display a remarkable cold resistant phenotype that is independent of brown and beige adipocyte function and is a result of increased skeletal muscle thermogenesis. We plan to use mouse genetics, metabolic profiling and physiologic assessments to determine the molecular basis for the cold resistance that occurs due to TIGAR deficiency. The specific novel aspects of our current findings are that: i) TIGAR deficiency does not affect energy production at room temperature but markedly enhances cold induced thermogenesis, ii) the increased thermogenic response is due to a direct activation of skeletal muscle ATP turnover through increased contractile activity and iii) the increased skeletal muscle contractile activity results from TIGAR deficiency in cholinergic neurons at the neuromuscular junction. A schematic representation of the mechanism(s) responsible for cold resistance in TIGAR knockout mice is illustrated and described in Figure 1. The specific novel aspects of the proposed research plan are: 1) to genetically determine whether TIGAR deficiency enhances skeletal muscle contraction based thermogenesis through increased cholinergic tone, 2) to determine whether the enhanced activation of skeletal muscle thermogenesis results from a loss of TIGAR protein dependent binding interaction(s) and/or due to a loss of TIGAR phosphatase activity, 3) to map the resultant changes in metabolic flux that occurs between thermoneutrality, room temperature and cold exposure in skeletal muscle, and 4) to identify the novel TIGAR-dependent molecular pathway responsible for the increase in cholinergic neuron signaling.
StatusActive
Effective start/end date1/1/907/31/22

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $305,466.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $39,130.00
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases: $343,686.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $351,869.00
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases: $338,608.00
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases: $351,869.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $343,686.00

ASJC

  • Genetics
  • Molecular Biology
  • Cell Biology
  • Endocrinology, Diabetes and Metabolism
  • Immunology

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