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We Are More Than What We
Eat: Dietary Interventions
Depend on Sex and Genetic
Background
Dudley Lamming, PhD
Medicine
University of Wisconsin-Madison
Associate Professor
We Are More Than What We Eat: Dietary
Interventions Depend on Sex and Genetic
Background
Dudley Lamming, Ph.D.
Associate Professor of Medicine, UW-Madison
Research Health Scientist, WSM VA Hospital
“Eat food. Not too much. Mostly plants.”
-Michael Pollan
What should I eat?
Calorie restriction extends the lifespan of mice and
non-human primates
Weindruch et al., 1986, Nutrition
Colman et al., 2014, N. Comms
“Tell me what you eat and I will tell you what
you are” - Anthelme Brillat-Savarin, 1826
• Low protein diets
cancer, mortality, and
diabetes
• Diabetes risk doubles
with increased
consumption of protein
• High protein diet
cardiovascular mortality
• Levine et al., 2014, Cell Metabolism
• Sluijs et al., 2010, Diabetes Care
• Lagiou et al., 2007, J Intern Med
A clinical trial of moderate protein restriction
Groups Intervention: 43 days
Protein restriction
(PR)
7-9% of calories from
protein
Control No dietary
modifications - 17% of
calories from protein
Gerald L. Andriole
Arnold D. Bullock
Robert S Figenshau
Beatrice Bertozzi
Edda Cava
Terri Pietka
Francesco Spelta
Valeria Tosti
Nicola Veronese
Washington University School of Medicine Clinical Trial Team, PI: Luigi Fontana
in 53 year old men with low-grade prostate cancer
A PR diet reduces weight, fat mass,
and fasting blood sugar
Calorie consumption is actually higher
in the PR group!
Protein restriction acutely improves metabolic
health in both humans and mice
Why study diets in mice?
• Mice eat exactly what we
feed them.
• We can measure exactly
how much they eat.
• We can control diet
composition precisely.
• We can do more tests.
Levine et al., 2014, Cell
Metab
Solon-Biet et al., 2014, Cell
Metab
Fontana et al., 2016, Cell Rep
Maida et al., 2016, JCI
Cummings et al., 2018, J
Physiol
Green et al., 2022, Cell
Metab
Ferraz-Bannitz et al.,
2022, Nutrients
The individual response to diet depends on genetic
background.
How does genetic background
contribute the response to dietary
protein?
We investigated how genetic
background and sex contribute to the
response to dietary protein
• We used 3 mouse strains
– C57BL/6J and DBA/2J (inbred)
– UM-HET3 (genetically heterogeneous F2s of 4 founder
strains)
• We used 3 diets
– Control (21% of calories from protein)
– Medium Protein (14% of calories from protein)
– Low protein (7% of calories from protein)
– Diets were isocaloric with identical levels of fat.
Sex and strain determine the effect of dietary
protein on weight gain
Green et al., 2022, Cell Metabolism
Sex and
strain
determine
the effect
of dietary
protein on
glucose
tolerance
Strain- and
sex-dependent
and
independent
physiological
and metabolic
responses to
dietary protein
Strain- and sex-dependent responses to
dietary protein
Sex, strain and
degree of
restriction
determines the
molecular
response to
dietary protein
B6 DBA
Variation between sexes and strains can give us
insight into molecular mechanism
FGF21 is an energy balance hormone produced in
response to fasting
Fgf21
Sex-specific roles for FGF21 in
response to dietary protein
FGF21 is an energy balance hormone produced in
response to fasting
Fgf21
Sex-specific roles for FGF21 in
response to dietary protein
Is FGF21 only important for the
response to PR in C57BL/6J males?
What is altered in a low protein diet that promotes
metabolic health?
Lynch, C. J. & Adams, S. H. (2014) Branched-chain amino acids in metabolic signalling and insulin resistance
Nat. Rev. Endocrinol. doi:10.1038/nrendo.2014.171
• Amino acids (AAs) are the building blocks of proteins.
• We used a series of synthetic, AA defined diets to
specifically examine the contribution of the essential
dietary amino acids.
Valine
Leucine Isoleucine
Dietary isoleucine and valine are potent regulators
of glucose tolerance
Yu, Richardson et al., 2021, Cell Metabolism
Mice fed a low isoleucine diet have improved
hepatic insulin sensitivity
Hyperinsulinemic-euglycemic clamp
Basal HGP Clamp HGP
Reducing dietary isoleucine blunts fat mass
accumulation
The metabolic effects of a Low BCAA
diet are recapitulated by specific
reduction of Ile or Val, not Leu
Yu, Richardson et al., 2021, Cell Metabolism
IleR promotes glucose tolerance across sexes and
strains
What are the physiological and molecular
mechanisms behind the effects of dietary
isoleucine on metabolic health?
A Low Ile diet promotes beiging of iWAT
FGF21 is required for some of the metabolic effects of a Low Ile
diet in C57BL/6J male mice
Yu, Richardson et al., 2021, Cell Metabolism
How do sex and genetic background
contribute to the effects of a Low Ile
diet?
A Low Ile diet
promote lower
body weight in
HET3 mice
Green et al., 2022, bioRxiv
A Low Ile diet
promotes
leanness in
HET3 mice
But HET3 mice fed Low AA or Low Ile diets eat more
So why do Low Ile fed mice weigh less?
Low AA and Low Ile diets promote
energy expenditure in HET3 mice
A low Ile diet promotes glucose tolerance in HET3
mice
Reducing dietary
isoleucine promotes
lifelong lower body
weight in HET3 mice
Reducing dietary isoleucine alters
lifelong body composition
A Low Ile diet promotes glucose tolerance in aged
HET3 mice
Male-specific effects of Low AA/Low Ile diets on
insulin sensitivity
Age and sex-dependent effects of a Low Ile diet
Low dietary isoleucine does not induce FGF21 in
HET3 mice
A Low Ile diet reduces frailty in HET3 mice
A Low Ile diet extends the lifespan of HET3 mice
Increased dietary isoleucine levels are associated
with higher BMI in Wisconsin residents
Analysis of data from SHOW (Survey of the Health of Wisconsin) and
WARRIOR (Winning the War on Antibiotic Resistance in Wisconsin)
Deelen et al., 2019,
Nature Communications
Sex and genetic background are critical
regulators of the response to dietary protein
NIA and NIDDK
(NIH)
R01AG056771
R01AG062328
R01DK125859
T32AG000213
F32AG077916
U01AG076941
William S.
Middleton
Memorial VA
Hospital
Nicole
Richardson
Sabrina
Dumas
Shany
Yang Matt
Wakai
Charles Yu
Victoria
Flores
Heidi
Pak
Collaborators
– Caroline Alexander & Ildiko
Kasza (UW)
– Joseph Baur (U. Penn)
– Dawn Davis (UW)
– John Denu (UW)
– Luigi Fontana (U. Sydney)
– Tim Hacker (UW)
– Troy Hornberger (UW)
– Cholsoon Jang (UC Irvine)
– Adam Konopka (UW)
– Teresa Liu and Will Ricke (UW)
– Kristen Malecki & SHOW (UW)
– Judith Simcox (UW)
Cara
Green
I01BX004031
Shelly
Sonsalla
Reji
Babygirija
Michaela
Murphy
Chung-Yang
Yeh
Mariah
Calubag
Leah
Braucher
Thank you for
participating!

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We Are More Than What We Eat Dietary Interventions Depend on Sex and Genetic Background

  • 1. Copyright 2022. All Rights Reserved. Contact Presenter for Permission We Are More Than What We Eat: Dietary Interventions Depend on Sex and Genetic Background Dudley Lamming, PhD Medicine University of Wisconsin-Madison Associate Professor
  • 2. We Are More Than What We Eat: Dietary Interventions Depend on Sex and Genetic Background Dudley Lamming, Ph.D. Associate Professor of Medicine, UW-Madison Research Health Scientist, WSM VA Hospital
  • 3. “Eat food. Not too much. Mostly plants.” -Michael Pollan What should I eat?
  • 4. Calorie restriction extends the lifespan of mice and non-human primates Weindruch et al., 1986, Nutrition Colman et al., 2014, N. Comms
  • 5. “Tell me what you eat and I will tell you what you are” - Anthelme Brillat-Savarin, 1826 • Low protein diets cancer, mortality, and diabetes • Diabetes risk doubles with increased consumption of protein • High protein diet cardiovascular mortality • Levine et al., 2014, Cell Metabolism • Sluijs et al., 2010, Diabetes Care • Lagiou et al., 2007, J Intern Med
  • 6. A clinical trial of moderate protein restriction Groups Intervention: 43 days Protein restriction (PR) 7-9% of calories from protein Control No dietary modifications - 17% of calories from protein Gerald L. Andriole Arnold D. Bullock Robert S Figenshau Beatrice Bertozzi Edda Cava Terri Pietka Francesco Spelta Valeria Tosti Nicola Veronese Washington University School of Medicine Clinical Trial Team, PI: Luigi Fontana in 53 year old men with low-grade prostate cancer
  • 7. A PR diet reduces weight, fat mass, and fasting blood sugar Calorie consumption is actually higher in the PR group!
  • 8. Protein restriction acutely improves metabolic health in both humans and mice Why study diets in mice? • Mice eat exactly what we feed them. • We can measure exactly how much they eat. • We can control diet composition precisely. • We can do more tests. Levine et al., 2014, Cell Metab Solon-Biet et al., 2014, Cell Metab Fontana et al., 2016, Cell Rep Maida et al., 2016, JCI Cummings et al., 2018, J Physiol Green et al., 2022, Cell Metab Ferraz-Bannitz et al., 2022, Nutrients
  • 9. The individual response to diet depends on genetic background. How does genetic background contribute the response to dietary protein?
  • 10. We investigated how genetic background and sex contribute to the response to dietary protein • We used 3 mouse strains – C57BL/6J and DBA/2J (inbred) – UM-HET3 (genetically heterogeneous F2s of 4 founder strains) • We used 3 diets – Control (21% of calories from protein) – Medium Protein (14% of calories from protein) – Low protein (7% of calories from protein) – Diets were isocaloric with identical levels of fat.
  • 11. Sex and strain determine the effect of dietary protein on weight gain Green et al., 2022, Cell Metabolism
  • 12. Sex and strain determine the effect of dietary protein on glucose tolerance
  • 14. Strain- and sex-dependent responses to dietary protein
  • 15. Sex, strain and degree of restriction determines the molecular response to dietary protein B6 DBA
  • 16. Variation between sexes and strains can give us insight into molecular mechanism
  • 17. FGF21 is an energy balance hormone produced in response to fasting Fgf21
  • 18. Sex-specific roles for FGF21 in response to dietary protein
  • 19. FGF21 is an energy balance hormone produced in response to fasting Fgf21
  • 20. Sex-specific roles for FGF21 in response to dietary protein Is FGF21 only important for the response to PR in C57BL/6J males?
  • 21. What is altered in a low protein diet that promotes metabolic health? Lynch, C. J. & Adams, S. H. (2014) Branched-chain amino acids in metabolic signalling and insulin resistance Nat. Rev. Endocrinol. doi:10.1038/nrendo.2014.171 • Amino acids (AAs) are the building blocks of proteins. • We used a series of synthetic, AA defined diets to specifically examine the contribution of the essential dietary amino acids. Valine Leucine Isoleucine
  • 22. Dietary isoleucine and valine are potent regulators of glucose tolerance Yu, Richardson et al., 2021, Cell Metabolism
  • 23. Mice fed a low isoleucine diet have improved hepatic insulin sensitivity Hyperinsulinemic-euglycemic clamp Basal HGP Clamp HGP
  • 24. Reducing dietary isoleucine blunts fat mass accumulation
  • 25. The metabolic effects of a Low BCAA diet are recapitulated by specific reduction of Ile or Val, not Leu Yu, Richardson et al., 2021, Cell Metabolism
  • 26. IleR promotes glucose tolerance across sexes and strains What are the physiological and molecular mechanisms behind the effects of dietary isoleucine on metabolic health?
  • 27. A Low Ile diet promotes beiging of iWAT
  • 28. FGF21 is required for some of the metabolic effects of a Low Ile diet in C57BL/6J male mice Yu, Richardson et al., 2021, Cell Metabolism How do sex and genetic background contribute to the effects of a Low Ile diet?
  • 29. A Low Ile diet promote lower body weight in HET3 mice Green et al., 2022, bioRxiv
  • 30. A Low Ile diet promotes leanness in HET3 mice
  • 31. But HET3 mice fed Low AA or Low Ile diets eat more So why do Low Ile fed mice weigh less?
  • 32. Low AA and Low Ile diets promote energy expenditure in HET3 mice
  • 33. A low Ile diet promotes glucose tolerance in HET3 mice
  • 34. Reducing dietary isoleucine promotes lifelong lower body weight in HET3 mice
  • 35. Reducing dietary isoleucine alters lifelong body composition
  • 36. A Low Ile diet promotes glucose tolerance in aged HET3 mice
  • 37. Male-specific effects of Low AA/Low Ile diets on insulin sensitivity
  • 38. Age and sex-dependent effects of a Low Ile diet
  • 39. Low dietary isoleucine does not induce FGF21 in HET3 mice
  • 40. A Low Ile diet reduces frailty in HET3 mice
  • 41. A Low Ile diet extends the lifespan of HET3 mice
  • 42. Increased dietary isoleucine levels are associated with higher BMI in Wisconsin residents Analysis of data from SHOW (Survey of the Health of Wisconsin) and WARRIOR (Winning the War on Antibiotic Resistance in Wisconsin)
  • 43. Deelen et al., 2019, Nature Communications
  • 44. Sex and genetic background are critical regulators of the response to dietary protein
  • 45. NIA and NIDDK (NIH) R01AG056771 R01AG062328 R01DK125859 T32AG000213 F32AG077916 U01AG076941 William S. Middleton Memorial VA Hospital Nicole Richardson Sabrina Dumas Shany Yang Matt Wakai Charles Yu Victoria Flores Heidi Pak Collaborators – Caroline Alexander & Ildiko Kasza (UW) – Joseph Baur (U. Penn) – Dawn Davis (UW) – John Denu (UW) – Luigi Fontana (U. Sydney) – Tim Hacker (UW) – Troy Hornberger (UW) – Cholsoon Jang (UC Irvine) – Adam Konopka (UW) – Teresa Liu and Will Ricke (UW) – Kristen Malecki & SHOW (UW) – Judith Simcox (UW) Cara Green I01BX004031 Shelly Sonsalla Reji Babygirija Michaela Murphy Chung-Yang Yeh Mariah Calubag Leah Braucher

Editor's Notes

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