Metabolism & Nutrition

I am using this space to put together my growing understanding of insulin resistance, cell biology of the gut, weight regulation, and nutrition.

I am a scientist (PhD Cell Biology) so my discussion here will be very specific regarding the cell biology, genomics, metabolomics, and other matters.

The material on this page will seem hodgepodge at first but will become more ordered but more complex over time.

If you have a question, by all means, leave a comment! I may or may not be able to answer your question now but may be able to later, once I have learned it myself.

This is what scientific inquiry is all about!

Glucagon-like peptide-1 (GLP-1), the small intestine, and gastric bypass surgery

There is an as yet to be understood relationship between the participation of the small intestine in the digestive process and the regulation of insulin as well as insulin receptivity of target cells.

We know of this relationship because patients who have had their small intestines by-passed in the weight loss surgery called Roux-en-Y anastomosis have improved insulin utilization but patients who have had the Lap-Band (adjustable gastric band) do not experience the same dynamic. (ref pending)

It is believed that GLP-1 (Glucagon-like peptide 1) is a critical molecule in this metabolic rescue.

The following graphic (source) provides some pathway context for the GLP-1 molecule in this setting.

WIKI-1000px-GLP1

Wiki says the following about GLP-1:

Glucagon-like peptide-1 (GLP-1) is derived from the transcription product of the proglucagon gene. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The biologically active forms of GLP-1 are: GLP-1-(7-37) and GLP-1-(7-36)NH2.

GLP-1 secretion by L cells is dependent on the presence of nutrients in the lumen of the small intestine. The secretagogues (agents that cause or stimulate secretion) of this hormone include major nutrients like carbohydrate, protein and lipid. Once in the circulation, GLP-1 has a half life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4. It is a potent antihyperglycemic hormone, inducing glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Such glucose-dependent action is particularly attractive because when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin to cause hypoglycemia. GLP-1 appears to restore the glucose sensitivity of pancreatic β-cells , with the mechanism possibly involving the increased expression of GLUT2 and glucokinase. GLP-1 is also known to inhibit pancreatic β-cell apoptosis and stimulate the proliferation and differentiation of insulin-secreting β-cells. In addition, GLP-1 inhibits gastric secretion and motility. This delays and protracts carbohydrate absorption and contributes to a satiating effects.

Adipogenesis

There are many tissue types in the body and each has its special method of developing over the lifetime of an organism and its own unique metabolism.

I am going to describe some of what is know about the development of the fat cell, a process we call “Adipogenesis”.

adip-2nd-msg

Nature Reviews Molecular Cell Biology 7, 885-896 (December 2006) doi:10.1038/nrm2066: Fig 3: Signals from activators and repressors of adipogenesis are integrated in the nucleus by transcription factors that directly or indirectly regulate expression of peroxisome proliferator-activated receptor (PPAR) and CCAAT-enhancer-binding protein (C/EBP). Some transcription factors (for example, cyclic AMP (cAMP) response element-binding protein (CREB)) function early in the programme of adipogenesis to regulate expression of C/EBP and PPAR, whereas others, such as GATA2/3 and SMAD3, physically interact with C/EBP to inhibit its transcriptional activity on the Pparg2 promoter. Insulin functions through at least four mechanisms to promote adipocyte differentiation; two of these mechanisms are common to other regulatory pathways (activation of CREB by cAMP and regulation of GATA factors in the sonic hedgehog (SHH) pathway). Activation of -catenin signalling is used by both Wnt-family proteins and androgens to repress adipogenesis. TGF inhibits adipogenesis through the phosphorylation of SMAD3, whereas bone morphogenetic protein-2 (BMP2) promotes adipogenesis by stimulating nuclear localization of Schnurri-2 (SHN2), SMAD1 and C/EBP. We have used + and – symbols to denote positive and negative effects on adipogenesis that are not understood mechanistically. AR, androgen receptor; FGF, fibroblast growth factor; FGFR, fibroblast growth-factor receptor; FOXO, forkhead protein; IGF1, insulin growth factor-1; IRS, insulin-receptor substrate; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3 kinase; PTC, patched; SMO, smoothened; TGF, transforming-growth factor . (source)

adipo-osteo

Nature Reviews Rheumatology 5, 442-447 (August 2009) | doi:10.1038/nrrheum.2009.137: Fig 2: MSCs (mesenchymal stem cells) are pluripotent cells capable of differentiating into cells of functionally distinct lineages. A number of regulators control MSC lineage fate. Humoral factors like Wnt ligands, BMP and TGF- transmit their signals through cognate cell membrane receptors expressed by the differentiating cells. Transcription factors often govern the final cell lineage decision during MSC differentiation, and their transcriptional activities are modulated through crosstalk with cell-membrane receptor-mediated signals. Abbreviations: BMP, bone morphogenetic protein; C/EBP, CCAAT/enhancer binding protein; GLI, GLI family zinc finger; KLF, Kruppel-like factor; MSC, mesenchymal stem cell; MYF, myogenic factor; MyoD, myogenic differentiation 1; NR3C1, nuclear receptor subfamily 3, group C, member 1; PPAR, peroxisome proliferator-activated receptor ; RUNX2, runt-related transcription factor 2; SOX, sex determining region Y-box; SHH, sonic hedgehog homolog; SP7, Sp7 transcription factor (formerly known as osterix); TGF-, transforming growth factor ; WWTR1, WW domain containing transcription regulator 1 (formerly known as TAZ).(source)

Recent refs re Adipogenesis:

  • Sumithra Urs, Deepak Venkatesh, Yuefeng Tang, Terry Henderson, Xuehui Yang, Robert E. Friesel, Clifford J. Rosen, and Lucy Liaw. Sprouty1 is a critical regulatory switch of mesenchymal stem cell lineage allocation. FASEB J. 2010 24: 3264-3273.

–more soon–