To learn more visit: https://insidescientific.com/webinar/we-are-more-than-what-we-eat-dietary-interventions-depend-on-sex-and-genetic-background/ Despite evidence that sex and genetic background are key factors in the response to diet, most studies of how diet regulates metabolic health and even longevity in mice examine only a single strain and sex. Using multiple strains and both male and female mice, Dr Lamming's team has found that improvements in metabolic health and in longevity in response to reduced levels of protein or specific amino acids strongly depend on sex and strain. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, they observed high variability in adiposity, insulin sensitivity, and circulating hormones. Using a multi-omics approach, they identified mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype, gaining new insight into role of the energy balance hormone FG21 in the response to protein restriction.

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

13. Strain- and
sex-dependent
and
independent
physiological
and metabolic
responses to
dietary protein

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

46. Thank you for
participating!