Gut, Nutrient Sensing and Energy Balance in Obesity

Gut, Nutrient Sensing and
Energy Balance in Obesity
Yunsook Lim, Ph.D
Department of Food and Nutrition
Kyung Hee University
Global Obesity
Obesity Prevalence in Korea
Obesity
Genetic
factors
Environmental
& Social factors
Interact on
Central
&
peripheral
Physiological
factors
Psychological
factors
OBESITY
Excessive fat accumulation
Low-grade chronic inflammation
Energy Balance
• A balance between energy intake and
energy expenditure
• Food intake: a key factor to control
energy intake
• A balance between the sensation of
hunger preceding a meal and the
sensation of fullness after nutrient
absorption.
Gut
• Digestive organs
• The first site of
interaction between
ingested nutrients
and the host
• Control of food
intake and regulation
energy balance
Nutrient Sensing in the Gut
• The largest endocrine organ in the body
• Produce over 20 hormones in spite of
enteroendocrine cells (EECs) being a small
representation(1%) of the total epithelial
cell population
• To the controls of food intake, termination
of a meal(satiation) and length of intermeal
interval(satiety)
• Co-expression of the gut peptides between
the various EECs
Gut-Brain Axis in Food Intake
Gut-Brain Axis in Food Intake
Brain
Gut
Simplified representation of potential action of gut peptides
on the hypothalamus
Energy Homeostasis via Gut-Brain
Axis in Obesity
• A dysregulated balance
between the sensation of
hunger preceding in a
meal and the sensation of
fullness after nutrient
absorption
• Modulation of gastric
distention, changes in gut
motility and the secretion
of gastrointestinal
hormones such as ghrelin,
cholecystokinin (CCK),
peptide YY3-36, glucagonlike peptide (GLP), and
oxytomodulin
Nutrient Sensing in the Gut
• Nutrients activate sensing mechanisms in the
duodenum to trigger a gut brain driven negative
feedback system to inhibit exogenous nutrient intake
and endogenous nutrient production by the liver.
• Metabolic homeostasis is maintained in the
response to nutrient intake.
• Intestinal nutrient sensing mechanisms fail to lower
food intake and glucose production, leading to a
disruption of metabolic homeostasis in obesity.
Gluconeogenesis in the Gut
•
Gluconeogensis is a new intestinal metabolic function.
•
Gut participates in the regulation of glucose homeostasis via its
capacity to uptake and metabolize glucose.
•
Glucose 6-phosphatase gene for gluconeogenesis is expressed in
the small intestine during fasting or insulin deficit condition such
as diabetes.
•
In particular, glucose in the portal vein initiates activation of vagal
nerve and activation of nerve in the nucleus of the solitary tract
and in the hypothalamus.
•
Glucose produced by gluconeogenesis in the gut leads to
regulation of food intake and energy homeostasis via portal
glucose sensing.
Protein Sensing in the Gut
• Protein enriched diets (PED) initiate satiety
effects indirectly via intestinal gluconeogenesis
and portal glucose sensing.
• PED induced genes related to gluconeogenesis.
• Peptides derived from the protein digestion in
the portal vein might be involved in μ-opioid
receptor (MOR) related control of food intake via
intestinal gluconeogenesis.
Lipid Sensing in the Gut
•
After absorption of lipids into
duodenal enterocytes, long
chain fatty acids (LCFA) from
lipids are metabolized into
LCFA-CoA by acyl-CoA
synthase.
•
Continuous intraduodenal
intralipids infusion elevates
duodenal LCFA-CoA levels
and lowers glucose
production.
•
Intraduodenal lipid
accumulation lowers food
intake through release of CCK.
Lipid Sensing in the Gut
• However, high fat
diet feeding causes
PKC-δ and CCK
resistance in lowering
glucose production.
• High fat diet induces
obesogenic
microbiota and
subsequently alters
CCK action.
Carbohydrates and Sugars
in the Gut
• Intestinal infusion of carbohydrates and
sugars have been reported to suppress
food intake which might be related to
secretion of gut peptides.
• The longer the length of the
carbohydrates infused, the greater the
reduction of food intakes (maltotriose vs
maltose).
The Gut Microbiota
• The entire microbial community
colonizing within the GI tract
• Interactive roles in influencing intestinal
nutrient absorption and sensing
• Aberrations in the gut microbiota: a
potential contributing factor in obesity
Gut Microbiota
Role of Gut Microbiota
Gut Microbiota in Obesity
Tremaroli and Backhed (2012) Nature 489; pp242-249
Obese Microbiota
Role of Gut Microbiota in Obesity
• Germ free (GF) mice have less adiposity
than normal mice, and are resistant to high
fat (HF) diet induced obesity.
• Increased AMP acivated protein kinase
(AMPK) in colonical epithelial cells and
hepatocytes in GF mice.
• GF mice colonized w/ microbiota derived
from an obese HF-fed donor results in an
increase in body.
Role of Gut Microbiota in Obesity
• The gut microbiota
derived lipopolysaccharides (LPS)
is associated with low
grade of inflammation
in obesity and
metabolic diseases.
• After only 2 weeks of
HF feeding, circulation
LPS levels were 2-3
fold increased in type
2 diabetes.
NASH/NAFLD
Tremaroli and Backhed (2012) Nature 489;
pp242-249
Dietary Fibers and
Gluconeogeneis in the Gut
•
Soluble dietary fiber is fermented by bacteria in the distal gut to
produce short chain fatty acids (SFA) including acetate, propionate
and butyrate.
•
Fiber enriched diets are known to improve insulin sensitivity and
glucose tolerance in lean and obese subjects.
•
The benefits of dietary fibers might come from SFA through
regulation of energy homeostasis.
•
In particular, propionate is a possible substrate of gluconeogenesis
and increases intestinal gluconeogenesis and portal glucose sensing.
•
Moreover, propionate stimulates gluconeogenesis related gene
expression via a portal hypothalamic neural circuit by activation of
the free fatty acid receptor(FFAR) whereas butyrate stimulate the
expression of gluconeogenesis related genes directly in the
enterocytes.
Summary
• The gut has multi-functions including controls of
food intake, gluconeogensis, hormone secretion
and nutrient sensing for energy homeostasis.
• Obese condition alters nutrient sensing
mechanisms and induces obese microbiota in
the gut.
• Rearrangement of an aberrant nutrient sensing
mechanism and obese microbiota would be a
potential therapeutic approach in obesity.
Thank you for your attention