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