OVERNUTRITION AND ADIPOSITY: Overnutrition contributes to chronic energy surplus leading to adiposity, IR, MetS and obesity with its fallouts including increased oxidative stress, altered glucose, fat and protein metabolism, and altered skeletal muscle mitochondrial function. REDOX BALANCE AND THIOREDOXIN SYSTEM: The cellular redox balance is regulated by activity of several antioxidant systems including TXN system. TNX is a key player in regulation of glucose homeostasis and lipid metabolism. The overexpression of TXNIP in T2DM, MetS and obese subjects is associated with metabolic abnormalities including apoptosis of β-cells, decreased insulin sensitivity and energy expenditure. The reduced oxidative capacity of skeletal muscle leads to accumulation of IMTG and affects mitochondrial function. TXNIP influences metabolic regulation mainly through insulin release from β-cells, glucose production from liver and glucose uptake in peripheral tissues. In addition, it acts as a nutrient sensor in discrete regions of brain. EFECTS OF CR ON METABOLIC HOMEOSTASIS: CR is a potentially effective therapeutic strategy to improve adiposity and insulin sensitivity at tissue level. CR associated weight loss decreases IMTG and improves mitochondrial function in skeletal myocytes. The decrease in adipose mass, oxidative stress and inflammation lead to downregulation of TXNIP, eliminating its inhibitory effect on glycolysis, glucose transporters, insulin receptors and receptor substrate, insulin-stimulated Akt activation and PI3K. CONCLUSION - NOVEL ADDITIVES TO POLYPHARMACY: The CR consistently leads to improved cardiometabolic outcomes and exerts beneficial effects on every organ system. Yet, CR is difficult to implement in practice for multiple reasons. Still, the focus on CR is important within a specific disease context to clearly delineate underlying mechanisms and exploit the research to achieve therapeutic goals. TXNIP is a potential therapeutic target. Anti-diabetic agents like metformin, GLP-1 agonists and CRMs like resveratrol inhibit TXNIP expression. Verapamil – a calcium channel blocker, tranilast - a tryptophan metabolite and allopurinol reduce TXNIP levels in vivo and in vitro studies. Lowering TXNIP levels halts β-cells apoptosis. On a cautious note, the loss of TXNIP may have serious consequences as TXNIP expression is required for maintaining normal fasting glycaemia and TXNIP being a tumour suppressor, its loss is associated with increased incidence of cancer.

2. Hindu Rao Hospital and NDMC Medical College, New Delhi India

3. My publication by same title in -
Research in Medical
& Engineering
Sciences
Published
On 03 October 2018.
DOI:
10.19080/OAJGGM.2018.04.555645
Also available on:
www.researchgate.net
DISCLOSURES
Fig 1-5 in this Presentation are
Subject to © Dr Vinod Nikhra.
FINANCIAL DISCLOSURES: None relevant.

4. Flow of the talk -
1. Basic concepts
2. Relevance of CR
3. Redox balance and TNX System
4. TNX system and Homeostasis
5. Therapeutic efficacy of CR
6. Therapeutic potential of TNXIP
7. Effect of CR on Gut Microbiome

5. To begin with CR –
Should not mean any kind of malnutrition or simply
undernutrition.
CR can be better defined as
CRAN = Caloric Restriction with Adequate Nutrition
or as
CRON = Caloric Restriction with Optimal Nutrition
DEFINING CALORIE RESTRICTION

6.  OVERNUTRITION: ingestion of food in excess causing a
mismatch between actual caloric requirement and intake,
resulting in chronic energy surplus.
 SALS: Modern-day sedentary activity lifestyle adds further to
the imbalance between calorie intake and energy expenditure.
 ADIPOSITY: The chronic energy surplus leads to adiposity -
accumulation of excess energy in adipose tissue as lipids,
contributing to IR, MetS and obesity with their fallouts.
 IR has been linked to increased OxS, altered glucose, fat and
protein metabolism, and altered skeletal muscle
mitochondrial function.
BASICS AND CONCEPTS

7. BASICS AND CONCEPTS ..2
OVERNRITION
leads to chronic energy surplus
Leading to adiposity, IR, MetS and Obesity
THE FALLOUTS OF OVERNUTRITION
Include -
 Altered skeletal muscle
mitochondrial function
 Altered glucose, fat and protein
metabolism
 Increased oxidative stress

8. Diet-gene interaction is an important determinant of health.
Rise in obesity and MetS prevalence in recent decades is attended
by background changes in dietary and lifestyle patterns - increased
nutrient consumption, and technology-assisted modern-day SALS of
daily living.
Fig 1. Adiposity: Overnutrition,
SALS and Chronic Energy
Surplus
BASICS AND CONCEPTS ..3

9. .
The pooling of positive energy balance leads to expansion
of WAT through increase in adipocytes volume as well as
trans-differentiation of new WAT from BAT to store
additional energy.
Fig 2. BAT → WAT to
store additional
energy
BASICS AND CONCEPTS ..4

10.  Consistent with pathophysiology of adiposity, MetS and
obesity, CR seems a potentially effective therapeutic
strategy to improve insulin sensitivity, reduce IR and
adiposity.
 CR reduces OxS and improves tissue functions in all
body organs, Better cardiometabolic outcomes.
 It decreases total skeletal muscle DAG and ceramide
content along with weight loss and improves
mitochondrial function in skeletal myocytes.
THE RELEVANCE OF CR

11. THE RELEVANCE OF CR ..2
Fig 3. Likely Mechanisms for CR to improve
Insulin Sensitivity and IR in Skeletal muscles,
and CR-TXNIP Link

12. THE RELEVANCE OF CR ..3
 Skeletal muscle is a major site of IR. IR is linked to mitochondrial
dysfunction and impaired fatty acid oxidation.
 With CR – carnosine, anserine, and taurine, potent scavengers of
lipid- and sugar-derived reactive carbonyl species (RCS), increase in
skeletal muscle.
 CR downregulates TXNIP – improves physiological
autophagy enhancing cellular metabolic fitness.

13.  REDOX BALANCE is regulated by activity of several antioxidant
systems including THIOREDOXIN SYSTEM. Here,
 Thioredoxin interacting protein (TXNIP) modulating the activity of
TXN, is a key player.
 TXNIP influences insulin release from β-cells, glucose production from
liver and glucose uptake in peripheral tissues.
 TXNIP also affects the general metabolism by acting as a nutrient
sensor in discrete regions of brain and playing a role
in the regulation of fuel utilization and
energy expenditure.
THE CONCEPT OF REDOX BALANCE

14.  The TXNIP plays a key negative regulator of insulin-stimulated glucose
uptake and influences metabolic regulation.
 Overexpression of TXNIP in T2DM, MetS and obesity is associated with
metabolic abnormalities including apoptosis of β-cells, decreased
insulin sensitivity and energy expenditure.
 The improvement in metabolic instability and insulin sensitivity
brought about by CR has been linked to the TXN system.
REDOX BALANCE AND TXN SYSTEM ..3

15.  There is β–cell loss and dysfunction of β–cells along with IR in DM. The β–cells
are susceptible to OxS and β–cell apoptosis results from enhanced TXNIP
expression in pancreatic islets following glucotoxicity.
 TXNIP inhibits glucose uptake by cells. It also upregulates expression of
miRNAs including miR-204 that mediate the inhibition of insulin production.
Fig 4. TXNIP associated
regulation of glucose
metabolism & related
projections
β–CELLS, OxS AND TXN SYSTEM

16. TXN SYSTEM AND HOMEOSTASIS
 TXNIP controls energy metabolism by regulating key processes in
adipose tissue, brain, liver, muscle and pancreatic β-cells.
 TXNIP is Nutrient Sensor and Regulator of metabolic homeostasis
and energy expenditure through hypothalamic and brainstem
centres. Its hypothalamic expression is repressed by feeding, insulin
and leptin, and stimulated during fasting.
 Improvement of insulin sensitivity in response to CR in obese
subjects results along with marked reduction of TXNIP levels in
skeletal muscle of obese adults.

17. TXN SYSTEM AND HOMEOSTASIS ..2
TXNIP functions through inhibition of TXN activity, which maintains a reducing
cellular environment.
Higher levels of ROS impairs β-cells function and reduce insulin sensitivity in
skeletal muscle and adipose.
Fig 5. Chronic Hyperglycemia
upregulates TXNIP impairing
β-cells Function

18.  TXNIP inhibits cellular glucose uptake by regulating glucose
transporter (Glut1).
 In addition, TXNIP also inhibits glucose uptake by inhibiting
glycolysis and increasing oxidative metabolism of pyruvate.
 TXNIP is also involved in NOD-like receptor Protein-3
inflammasome activation. NLRs detect signals from cells
undergoing stress, damage or apoptosis.
 TXNIP initiated NLRP3 inflammasome activation enhances
obesity-induced insulin resistance and β-cells
failure.
TXN SYSTEM AND HOMEOSTASIS ..3

19.  Upregulation of TXNIP is a short-term response to high calories diet.
Long term, over-nutrition leads to permanent increase in TXNIP
expression.
 TXNIP binds with Glut to regulate its endocytosis and interacts with
glucose transporters in insulin sensitive adipose and
muscle tissues.
 TXNIP inhibits glycolysis by downregulating the glycolytic
enzymes.
 TXNIP activates Phosphatase and Tensin homolog (PTEN) lipid
phosphatase by REDOX-sensitive mechanism to negatively
regulates glucose uptake and metabolism.
TXN SYSTEM AND HOMEOSTASIS ..4

20. CR consistently leads to improved cardiometabolic outcomes and
exerts beneficial effects on every organ system. The focus on CR is
important within a specific disease context to achieve therapeutic
goals. CR is an aid in planning better treatment strategies and fulfilling
therapeutic targets.
CR may involve cutting down the caloric intake by about 40 percent
with provision for adequate dietary protein and essential elements like
vitamins and minerals.
Yet, CR is simple to conceptualize and difficult to implement in clinical
practice. Convincing to follow and adhere to the rigid dietary program
and dealing with fear about compromised QOL
are prime issues.
THERAPEUTIC POTENTIAL OF CR

21. CR is a potentially effective therapeutic strategy to improve
adiposity and insulin sensitivity & action at tissue level.
CR associated weight loss decreases IMTG and improves
mitochondrial function in skeletal myocytes.
Decrease in adipose mass, OxS and inflammation lead to
downregulation of TXNIP, eliminating its inhibitory effect on
glycolysis, glucose transporters, insulin receptors and receptor
substrate, insulin-stimulated Akt activation and PI3K.
THERAPEUTIC EFEICACY OF CR

22.  CR: As additive to polypharmacy consistently leads to improved
cardiometabolic outcomes, exerts beneficial effects on every organ.
Yet, CR may seem difficult to implement as a long-term therapy in
obese patients for multiple reasons like dietary adherence,
perceived decrease in QOL.
 Further, CR being difficult to implement in practice, still the focus on
CR is important within a specific disease context to achieve
therapeutic goals.
 We have to discover effective and suitable measures
to facilitate implementation of CR.
THERAPEUTIC IMPLEMENTATION OF CR

23.  The TXNIP is an important player in regulating insulin sensitivity of
peripheral tissues, its overexpression causing reduced insulin
sensitivity.
 Insulin, metformin and CR mimetics like resveratrol are known
activator of AMPK, which in turn inhibits expression of TXNIP mRNA
and augments degradation of TXNIP protein.
 Overexpression of TXNIP is associated with abnormalities such as β-
cells apoptosis, IR and decreased energy expenditure.
 GLP-1 receptor agonists regulate expression of TXNIP by accelerating
its proteosomal degradation in a cAMP/PKA dependent
manner.
THERAPEUTIC POTENTIAL OF TXNIP

24. TXNIP is, thus, another potential therapeutic target. Anti-diabetic
agents like metformin, GLP-1 agonists and CRMs like resveratrol
inhibit TXNIP expression.
Verapamil – a calcium channel blocker, tranilast - a tryptophan
metabolite and allopurinol reduce TXNIP levels in vivo/in vitro
studies. May protect β-cells from apoptosis.
On a cautious note, the loss of TXNIP may have serious
consequences as TXNIP expression is required for maintaining
normal fasting glycaemia and TXNIP being a tumor suppressor,
its loss may be associated with ↑ cancer risk.
THERAPEUTICALLY TARGETING TXNIP