This document summarizes a lecture on the roles of muscle, white adipose tissue (WAT), and liver in metabolic flexibility. It discusses how these tissues function normally and how dysfunctions can lead to conditions like fatty liver disease. Specifically, it describes:
1) The normal functions of muscle, WAT, and liver related to metabolism and how dysfunctions can cause diseases.
2) Studies on non-alcoholic fatty liver disease (NAFLD) and how communication between WAT and liver is essential for lipid storage.
3) Research on the effects of high-protein diets on hepatic lipid accumulation and gene expression changes in the gut-liver axis.
4) How exercise increases heart rate
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Role of Liver, Muscle and Fat Tissue Metabolism
1. Lecture 3
From healthy to too much
The role of Muscle, WAT, Liver for metabolic flexibility
Michael Müller
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University
11. WAT Functions related to Nutrition
1. Lipolysis
2. Lipogenesis (TG)
3. Maintaining triglyceride and free fatty acid levels
& determining insulin resistance
4. Protecting other organs from lipotoxicity
12. WAT dysfunctions related to nutrition
1. Overweight, Obesity, Metabolic
syndrome, Diabetes, CVD, Cancer….
2. Abdominal fat has a different metabolic
profile & being more prone to induce
insulin resistance.
3. Central obesity is a marker of impaired
glucose tolerance & is an independent
risk factor for cardiovascular disease
13. de Wit NJ, Afman LA, Mensink M, Müller M
Phenotyping the effect of diet on non-alcoholic
fatty liver disease J Hepatol 2012
.
21. Liver, FAT & NASH/NAFLD
Nonalcoholic Fatty Liver Diseases (NAFLD):
Liver component of Metabolic Syndrome
Different stages in NAFLD progression:
Molecular events involved in NASH pathogenesis:
Role of PPARa (Endocrinology 2008 & Hepatology 2010)
Role Kupffer cells (Hepatology 2010)
Role of macrophages in lipid metabolism (JBC 2008; Cell Metabolism 2010)
hepatic steatosis steatohepatitis (NASH) & fibrosis cirrhosis
22. Interaction between WAT and liver tissue
essential for NASH/NAFLD in C57Bl/6 mice
Objective:
– Nonalcoholic fatty liver disease (NAFLD) is
strongly linked to obesity and diabetes,
suggesting an important role of adipose tissue
in the pathogenesis of NAFLD.
– Here we aimed to investigate the interaction
between adipose tissue and liver in NAFLD,
and identify potential early plasma markers
that predict NASH.
31. Plasma proteins as early predictive
biomarker for NASH in C57Bl/6 mice
Multivariate analysis of association of protein
plasma concentrations with final liver
triglyceride content
32. Conclusions
• The data support the existence of a tight
relationship between adipose tissue
dysfunction and NASH pathogenesis.
• It points to several novel potential
predictive biomarkers for NASH.
34. Objective
Investigating the effect of a high protein diet on
hepatic lipid accumulation.
Unravel mechanisms which are responsible for
the reduced liver fat.
35. Design & diets
1 week 12 weeks
Acute effect
of a high fat /
high protein diet
Long term diet effect
on the development
of liver steatosis
2 weeks
Run-in:
control diet
Experimental diets Carbohydrate (en%) Fat (en%) Protein (en%)
Two low fat diet – normal or high protein
LF-NP 75 10 15
LF-HP 40 10 50
Two high fat diet – normal or high protein
HF-NP 50 35 15
HF-HP 15 35 50
45. Interplay between adipokines and
myokines represent a yin–yang balance
Pedersen, B. K. & Febbraio, M. A. (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ
Nat. Rev. Endocrinol. doi:10.1038/nrendo.2012.49
Inflammation has been associated with many disease phenotypes including steatohepatitis or diabetes. This relationship is in particular when inflammation is chronic or non-resolving. There is an interaction between metabolism and inflammation with positive or negative consequences with respect to organ and systemic health.In my talk I will briefly discuss two unpublished studies, one investigating the important interaction of WAT and liver in particular under conditions of diet-induced obesity. Organ-specific macrophages in WAT and liver play an crucial role in progressing organ-specific inflammatory phenotypes. In the second study we found very interesting interaction between dietary fat and macrophages in mesenteric lymph nodes that are exposed postprandially to very high concentrations of chylomicrons. We used a k.o. mouse for ANGPTL4 and could show that chronic consumption of saturated fat can be deadly.
A subpopulation of mice fed HFD develops NASH. Haematoxylin and eosin staining (D) and oil red O staining (E) of representative liver sections of the 4 subgroups
(Immuno)histochemical staining confirms enhanced inflammation and early fibrosis in HFH miceImmunohistochemical staining of macrophage activation in representative liver section of HFL and HFH mice using antibody against the specific macrophagemarker Cd68Collagen staining using fast green FCF/sirius red F3B. Staining of stellate cell activation using antibody against GFAP.
- Number of genes up- or down-regulated in the various subgroups in comparison to the LFL mice, as determined by Affymetrix GeneChip analysis. Genes with a p-value below 0.05 were considered significantly regulated. - Heat map showing changes in expression of selected genes involved in lipid metabolism, inflammation and fibrosis in liver. Changes in gene expression of selected genes as determined by real-time quantitative PCR. Mean expression in LFL mice was set at 100%. Error bars reflect standard deviation. Bars with different letters are statistically different (P<0.05 according to Student’s t-test). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
Haematoxylin and eosin staining of representative adipose tissue sections. Immunohistochemical staining of macrophages using antibody against Cd68. Collagen staining using fast green FCF/sirius red F3B.
Adipose tissue mRNA expression of a selected group of genes was determined by quantitative real-time PCR after 21 weeks of dietary intervention. Mean expression in LFL mice was set at 100%. Error bars reflect standard deviation. * = significantly different from HFL mice according to Student’s t-test (P<0.05). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
. A) Plasma concentration of haptoglobin, TIMP-1, IL-1β, leptin and insulin were determined by multiplex assay at specific time points during the 21 weeks of dietary intervention after a 6h fast. White squares: LFL, Light grey squares: LFH, dark grey squares: HFL, black squares: HFH. Error bars reflect standard deviation. * = significantly different from HFL mice according to Student’s t-test (P<0.05). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
Graphs illustrating the result of multivariate analysis showing the association of protein plasma concentrations at various time points with final liver triglyceride content. Significant proteins display an inverse RSD value higher than 2 (bold line indicates the inverse RSD threshold value of 2).RSD = Relative standard deviation.
Dietary amino acids are firstly used for protein synthesis; however, this can only happen to a limited extent. Subsequently, carbon skeletons can be utilised for gluconeogenesis in a very limited amount. An overload of the liver with dietary amino acids promotes catabolism to acetyl-CoA. Synthesised acetyl-CoA is either channelled into the TCA cycle or used for BHB production. With increasing ingestion of protein, amino acid oxidation and production of BHB from acetyl-CoA becomes more important in relation to gluconeogenesis and protein synthesis.