TMM4308

Hormonal Regulation of Energy Metabolism

Dietary Regulation of Metabolism

Han Kim
Scientist, University of Ottawa Heart Institute
Associate Professor, Department of Cellular and Molecular
Feb 4, 2020Medicine
University of Ottawa
N Engl J Med. 2019 Dec 26;381(26):2541-2551
 OUTLINE of Today’s lecture
• Introduction to dietary interventions

• Caloric restriction vs. Eating pattern change

• Intermittent fasting

• Time-restricted feeding

• Fasting-mimicking diet

• Ketone body

• The effects of sex and age in dietary intervention

• Dietary intervention in humans

Classification of dietary interventions

Front Genet. 2020 Oct 15;11:590369

Caloric restriction

Eating pattern change

 Erratic eating patterns in modern humans
The daily intake duration exceeded 14.75 hr

(Cell Metabolism, 2015)

Shorter fasting period à increased obesity and metabolic diseases

Fasting extended lifespans of bacteria, yeast, worms and mice

Cell Metab. 2014 Feb 4;19(2):181-92

Cellular Responses to Energy Restriction

N Engl J Med. 2019 Dec 26;381(26):2541-2551

 The beneficial effects
of fasting
against…

• Aging
• Cancer
• Cardiovascular diseases
• Neurodegenerative
diseases
• Metabolic dysfunctions

How can we practice fasting?

 Periodic fasting Intermittent fasting
2 or more days of fasting, Up to 24 hr fasting, followed
separated by at least 1 week by normal feeding of 1-2 days
 Fasting-based dietary interventions

Periodic fasting – Intermittent fasting – Time-restricted fasting

caloric restriction on a caloric restriction on a – caloric restriction on
weekly/monthly basis daily basis an hourly basis
Most of previous studies used ‘alternate-day fasting’

Feeding

1 2 3 4 5 6 …
Fasting
Isocaloric 2:1 intermittent fasting protects mice from obesity

(Kim et al., Cell Res. 2017 Nov;27(11):1309-1326)

Isocaloric 2:1 intermittent fasting protects mice from obesity

(Kim et al., Cell Res. 2017 Nov;27(11):1309-1326)

Adipose-derived factors in IF-treated white adipose tissues
Increased vasculature in white adipose tissues after IF
Adipose-VEGF Is required for IF-mediated metabolic benefits
Adipose-VEGF Is sufficient to mimic the IF-mediated metabolic benefits
Adipose-VEGF Is sufficient to mimic the IF-mediated metabolic benefits
IF mice show increased M2 macrophage in white adipose tissues
VEGF OE mice show increased M2 macrophage in white adipose tissues
One-time fasting or VEGF induction can induce M2 macrophage polarization
Adipose-VEGF induced WAT browning requires adipose macrophages
VEGF expression in human adipose tissues positively correlates with M2
macrophage and WAT Browning
Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by
Shaping the Gut Microbiota

Cell Metab. 2017 Oct 3;26(4):672-685

Intermittent Fasting alters gut microbiota

Cell Metab. 2017 Oct 3;26(4):672-685

Gut microbiota mediates the effect of intermittent fasting

• Control vehicle (CV)

• Antibiotics cocktail (AB)
• Microbiota transplantation (MT)

Cell Metab. 2017 Oct 3;26(4):672-685

Increased adipose thermogenesis by intermittent fasting

Cell Res. 2017 Nov;27(11):1300-1301

Thermogenesis-independent metabolic benefits of
intermittent fasting in leptin-deficient mice

Sci Rep. 2019 Feb 21;9(1):2479

Thermogenesis-independent metabolic benefits of
intermittent fasting in leptin-deficient mice

Sci Rep. 2019 Feb 21;9(1):2479

Time-restricted feeding
Time-restricted feeding is a preventative and therapeutic intervention
against diverse nutritional challenges

Cell Metab. 2014 Dec 2;20(6):991-1005

Time-restricted feeding is a preventative and therapeutic intervention
against diverse nutritional challenges

Cell Metab. 2014 Dec 2;20(6):991-1005

Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in
Mice Lacking a Circadian Clock

Cell Metab. 2019 Feb 5;29(2):303-319

Fasting-mimicking diet
Fasting-mimicking diet (FMD)

Dr. Valter Longo

(Univ. of Southern California)

• Average male adult needs 2,500 Kcal

• FMD = 3000 – 4600 KJ per day (= 700 – 1100 Kcal)
• 5 consecutive days of FMD per month for 3 month
 A Periodic Diet that Mimics Fasting Promotes Multi-System
Regeneration, Enhanced Cognitive Performance, and Healthspan

Cell Metab. 2015 Jul 7;22(1):86-99

Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to
Reverse Diabetes

Cell. 2017 Feb 23;168(5):775-788

Fasting-Mimicking Diet Modulates Microbiota and Promotes Intestinal
Regeneration to Reduce Inflammatory Bowel Disease Pathology

Cell Rep. 2019 Mar 5;26(10):2704-2719

A Diet Mimicking Fasting Promotes Regeneration and Reduces
Autoimmunity and Multiple Sclerosis Symptoms
Murine experimental autoimmune encephalomyelitis (EAE) model

Cell Rep. 2016 Jun 7;15(10):2136-2146

Fasting vs. caloric restriction
Why all these dietary interventions provide
similar benefits?
Plasma energy substrates during fasting
Ketone bodies metabolism

Cell Metab. 2017 Feb 7;25(2):262-284

Noncanonical signaling roles of ketone bodies

Cell Metab. 2017 Feb 7;25(2):262-284

Impaired ketogenic activity in HFD-induced NAFLD mice

(Asif, Mol Metab, 2022)

Loss of ketogenesis causes spontaneous fatty liver disease

(Asif, Mol Metab, 2022)

Ketosis ameliorates non-alcoholic fatty liver disease (NAFLD)

(Asif, Mol Metab, 2022)

Ketosis ameliorates non-alcoholic fatty liver disease (NAFLD)

(Asif, Mol Metab, 2022)

Ketogenic diet
Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease

Cell Metab. 2019 Dec 3;30(6):1007-1023

Ketosis activates metabolically protective γδ T cells in adipose tissues

Nat Metab . 2020 Jan;2(1):50-61

Long-term ketone diet induces obesity and metabolic dysfunction

Nat Metab . 2020 Jan;2(1):50-61

Nutritional Ketosis Alters Fuel Preference and Thereby Endurance
Performance in Athletes

Cell Metab. 2016 Aug 9;24(2):256-68

 Ketone ester

Elevates blood ketone levels to 3-5 mM in 30 minutes without a salt, acid, or fat load.
Do these dietary interventions work against
aging?
Age-associated adipose fibrosis

ageing / obesity
Adipose single cell analysis – Single cell sequencing
Old-Control Old-IF

APC APC

Cluster #1 Cluster #1

(Manuscript in preparation)
Daily Fasting Improves Health and Survival in Male Mice Independent
of Diet Composition and Calories

Cell Metab. 2019 Jan 8;29(1):221-228

A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice

Cell Metab. 2017 Sep 5;26(3):539-546

Cyclic Ketogenic Diet Reduces Midlife Mortality and Improves Memory
in Aging Mice

Cell Metab. 2017 Sep 5;26(3):547-557

Does these dietary interventions work
for both male and female?
Sex-dependent outcomes of IF against HFD-induced obesity

(Asif and Aslani et al., Unpublished data)

Sex-dependent outcomes of time-restricted feeding of HFD

(Chaix et al., Cell Reports 36, 109543)

Sex difference in hepatic lipid metabolism during fasting
Sex difference in hepatic lipid metabolism during HFD

(Mol Metab. 2020 Feb;32:97-108)

Ketogenic genes HMGCS2 is negatively associated with inflammation in the liver

(Asif and Aslani et al., Unpublished data)

Ketogenic genes HMGCS2 is negatively associated with inflammation in the liver
with sex differences

(Asif and Aslani et al., Unpublished data)

Association between plasma ketone bodies and fatty liver disease

(Asif and Aslani et al., Unpublished data)

Do these dietary interventions work in humans?
Alternate Day Fasting Improves Physiological and Molecular Markers of Aging
in Healthy, Non-obese Humans

Cell Metab. 2019 Sep 3;30(3):462-476

Cell Metab. 2020 Sep 1;32(3):366-378
Fasting-mimicking diet and markers/risk factors for aging, diabetes,
cancer, and cardiovascular disease

Sci Transl Med. 2017 Feb 15;9(377)

Systemic proteome adaptions to 7-day complete caloric restriction in humans

Pietzner, et al, Nature Metabolism, 2024

Do these dietary interventions work against cancer?
Influence of Dietary Carbohydrates on Tumor Metabolism
Fasting induces differential stress sensitization in cancer treatment

PLoS One. 2012;7(9):e44603

PLoS Biol. 2017 Mar 30;15(3):e2001951
5:2 intermittent fasting starves cisplatin-resistant cancers to death

EMBO J. 2018 Jul 13;37(14)

Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates
BRAF V600E Tumor Growth

Cell Metab. 2017 Feb 7;25(2):358-373

Fasting mimicking diet and hormone therapy induce breast cancer regression

• Fasting or FMD potentiates the activity of ET in HR+ BC by

reducing circulating growth-promoting factors
• FMD prevents resistance to combined fulvestrant and
palbociclib

TMX (Tamoxifen)
FULV (fulvestran)

Nature. 2020 Jul;583(7817):620-624

Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast
cancer in the multicentre randomized phase 2 DIRECT trial

• A radiologically complete or partial response

occurs more often in patients using the FMD
(OR 3.168, P = 0.039).

• Moreover, per-protocol analysis reveals that

the Miller&Payne 4/5 pathological response,
indicating 90–100% tumor-cell loss, is more
likely to occur in patients using the FMD (OR
4.109, P = 0.016).

• The FMD significantly curtails chemotherapy-

induced DNA damage in T-lymphocytes.

Nat Commun . 2020 Jun 23;11(1):3083

 Early downmodulation of tumor glycolysis predicts response to
fasting-mimicking diet in triple-negative breast cancer patients

• Cyclic FMD plus preoperative chemotherapy results in

excellent pathologic complete response (pCR) rates in
stage I–III TNBC patients.

• In tumors achieving pCR, bulk and single-cell RNA-seq

analysis revealed early downmodulation of glucose
metabolism in TNBC cells and in glycolytic intratumor
cells.

Cell Metab. 2025 Feb 4;37(2):330-344

 OUTLINE of Today’s lecture
• Introduction to dietary interventions

• Caloric restriction vs. Eating pattern change

• Intermittent fasting

• Time-restricted feeding

• Fasting-mimicking diet

• Ketone body

• The effects of sex and age in dietary intervention

• Dietary intervention in humans