Units of Life Seminar Series - Lecture by Paul Cohen

Introduction - Anna

• Welcome to the Units of Life Seminar Series.
• Focus: deeper mechanistic biology beyond omic technologies.
• Initiated by Anna and Gillian Shaw.
• Seminar series runs approximately once a month.
• Notable upcoming speakers: John Brugie, Helen Hobbs, Anna Maria Corvo, Arlene Sharpe.

Speaker Introduction - Paul Cohen

• Albert Resnick Associate Professor at Rockefeller University.
• Head of the Laboratory of Molecular Metabolism.
• Educational and professional background: Harvard College (AB), tri-institutional MD/PhD program (Rockefeller), residency (Columbia), fellowship training (Brigham and Farber), faculty at Rockefeller.
• Research focus: adipocyte biology, intersection of cardiology and cancer, intercellular crosstalk related to obesity.

Paul Cohen's Presentation: The Role of Brown Fat in Obesity and Related Comorbidities

Overview

• Major biomedical problem: obesity.
• By 2030, 50% of US adults expected to be obese.
• Global issue: diseases due to overnutrition surpassing those due to undernutrition.
• Comorbid diseases linked to obesity: heart disease, diabetes, kidney disease, cancer, worse COVID-19 outcomes.

Patient Examples

• 75-year-old man: obesity, multiple cardiovascular issues, rectal cancer.
• 52-year-old woman: obesity, multiple cancers, cardiovascular issues.
• Question: How does obesity lead to these comorbid conditions?

Research Focus Areas

1. White Fat Biology
2. Potential of Brown Fat in Unlinking Obesity from Disease

Adipocyte Biology

• White Fat Cells: Store excess calories, large unilocular lipid droplets, mobilize energy through lipolysis.
• Brown Fat Cells: Dissipate energy as heat, small multilocular lipid droplets, high number of mitochondria, uncoupled thermogenesis.

Uncoupled Thermogenesis

• Mechanism:
  • Proton gradient used by ATP synthase disrupted by UCP1 (Uncoupling Protein 1).
  • Results in dissipation of energy as heat.
• Mouse Studies:
  • Ablation of UCP1 results in cold intolerance and obesity.
  • Brown fat aids in clearing toxic metabolites.
• Evolutionary Role of Brown Fat: Protects newborn mammals from hypothermia.

Human Brown Fat

• Adult humans have cold-inducible brown fat.
• FDG PET CT scans show cold-induced brown fat activity.
• Retrospective and prospective studies link brown fat to metabolic benefits.

Large-Scale Study - Retrospective Analysis

• Dataset: Over 50,000 patients, 130,000 scans.
• Brown fat associations: Reduced odds of type 2 diabetes, coronary artery disease, congestive heart failure, hypertension.
• Effects independent of BMI.

Detailed Analysis - Regional Distribution and Function

• Different white fat distributions linked to brown fat presence.
• Brown fat associated with lower visceral fat and healthier liver fat profiles.

Mechanisms of Thermogenic Fat

1. Form: Cellular components and structures of thermogenic fats.
2. Function: How brown fat communicates with other tissues.
3. Regulation: Genetic determinants of thermogenic fat.

Techniques and Discoveries

• Adipo-Clear:
  • 3D visualization of adipose tissue.
  • Revealed regional distribution of beige adipocytes.
• Sympathetic Nervous System Role:
  • Cold sensed by neurons activates thermogenic response via catecholamines.
• Findings: Deletion of PRDM16 affects nerve density in adipose tissues.

Proteomic Studies

• BONCAT Technique: Tagging newly synthesized proteins to identify secreted factors from brown and beige fat.
• Identification of Novel Proteins: Unique proteins secreted by different types of adipocytes.
• In Vivo Studies: Use of mutant methionine tRNA synthase models to study protein secretion in physiological states.

Human Studies

• Cold Vest Study: Profiling plasma protein and metabolite changes post cold exposure.
• Future Study: Minneapolis Ice Water Immersion Study to explore effects of chronic cold exposure on adipose tissue.

Genetic Studies

• Investigating genetic variants associated with high brown fat activity or age-retained brown fat.
• Collaborations with Turkish Obesity Study and thin phenotype cohort in the UK.

Conclusion

• Brown fat linked to protection against cardiometabolic diseases.
• Understanding form, function, and regulation could lead to new therapies to unlink obesity from related comorbidities.
• Acknowledgements to collaborators and lab members.

Q & A Highlights

• Activating PRDM16: Potential via small molecules targeting regulatory mechanisms.
• Exercise and Brown Fat: No study data on exercise, but recent findings suggest no activation with exercise in humans.
• Neurodegenerative Disease: Ongoing studies on links between brown fat and cognitive performance.
• Importance of Thermogenic Contributions: Skeletal muscle shivering vs. brown fat endocrine role.
• Additional Questions: Correlation between brown fat quantity and genetic variabilities in inducible brown fat.