Coll's "The hormonal control of food intake" 2007

From Biol557

Contents 1 Abstract 2 Introduction 3 Leptin 3.1 Developmental effects of leptin 3.2 Mechanisms of leptin resistance 3.3 What regulates leptin secretion? 4 Other signals from adipocytes 5 The GI tract 5.1 Cholecystokinin (CKK) 5.2 PYY 5.3 Ghrelin 5.4 Obestatin 5.5 Glucagon-like peptdie 1 5.6 Oxyntomodulin 6 The pancreas 6.1 Insulin 6.2 Pancreatic polypeptide 7 Other sites 8 Summary

[edit] Abstract

• Lots of circulating peptides and hormones affect appetite by action on the hypothalamus and brain stem.
• These factors come, primarily, from adipose tissue, the GI tract, and the pancreas.

[edit] Introduction

• There must be a calorie intake mechanism because while our food intake fluctuates we maintain a constant body weight.
• Old-timey experiments with ablation of the hypothalamus in mice showed it to be important in this process because some overate after intervention.
• "We no know that a number of circulating peptides and steroids that are produced in the body can have a substantial influence on appetitive behavior through their actions on the hypothalamus, the brain stem, or afferent autonomic nerves."
• "These hormones come from at least three sites: fat cells, the gastrointestinal tract, and the endocrine pancreas."

[edit] Leptin

• Leptin and its receptor OB-R activate the Jak-Stat pathway in the hypothalamus.
  • As signaling increases, hunger satiation occurs and food intake stops.
• Many mutations in leptin and OB-R have been found in patients that suffer from obesity.
• Leptin has drastic effects in mouse models of obesity but only minor effects in most obese humans.
  • The exception is patients with leptin-deficiency, in which leptin administration is life-saving.
• There is still a lot we don't know about leptin like where it signals and how it is regulated and where it is secreted.
• We do know there is a specific population of cells in a specific nucleus of the hypothalamus that seem to respond to leptin.
• Leptin signaling affects POMC, melanocortin receptors, and BDNF / TrkB.

[edit] Developmental effects of leptin

• Leptin is a key regulator of neuronal synaptic development and plasticity in the hypothalamus.
• Note, however, that even if leptin is deficient during development, adults are able to respond to the administration of leptin.

[edit] Mechanisms of leptin resistance

• Three mechanisms have been seen: lack of leptin circulation, decrease in leptin expression, and inhibition of Jak-Stat intracellular signaling upon leptin stimulation.
• The intracellular signaling inhibition is a function of Socs3 (suppressor of cytokine signaling 3).
• We continue to have a hard time researching leptin signaling disorders because the tissue of the receptor expression is so hard to access (the hypothalamus) and the neuronal cells that express the leptin receptor are likely mixed in populations with non-lepticn-receptor-expression neurons.

[edit] What regulates leptin secretion?

• "The amount of leptin produced by an adipocyte appears to be regulated at the transcriptional level but also at the levels of translation, storage, turnover, and secretion"
• "Insulin and glucocorticoids positively regulate leptin production whereas agents that increase cAMP levels in the adipocyte, such as β adrenergic agonists, suppress leptin production"
• Androgens suppress leptins which explains gender differences in base levels of leptin.
• It is unclear how fat stores signal to the adipose tissue to produce more leptin.

[edit] Other signals from adipocytes

• Adiponectin looks like TNFalpha and collagen and is negatively correlated with weight: less adiponectin is seen in lite mice and more is seen in obese mice.
• Interluekins: IL6 is released from the fat around the bowels and follows the leptin association with weight.
  • IL6 / IL1 deficiency causes hyperphagia.

[edit] The GI tract

[edit] Cholecystokinin (CKK)

• CCK is released by the enteroendocrine cells of the duodenum and jejunum.
• CCK is released in response to fatty acids.
• CCK is a peptide.
• CCK acts on receptors at the vagal afferent terminals which transmit signals to appetite centers in the brain stem.
• MC4R is the CCK receptor.

[edit] PYY

• PYY is a peptide released by endocrine cells of the gut which serves to decrease appetite when administered peripherally or to increase appetitde upon central administration.

[edit] Ghrelin

• A peptide produced by oxyntic cells of the stomach that signals though the GHSR to increase food intake.

[edit] Obestatin

• Obestatin results from slightly different enzymatic processing of the ghrelin precursor and directly opposes the actions of ghrelin.

[edit] Glucagon-like peptdie 1

• Glucagon-like peptdie 1 is released by L cells in the gut upon food stimulation.
• GLP1 potently induces the release of insulin.

[edit] Oxyntomodulin

• Generated from the proglucagon gene (as is GLP1), oxyntomodulin is released by the small intestine upon meal stimulation.
• It acts to reduce gut motility and secretion.

[edit] The pancreas

[edit] Insulin

• "Insulin receptors are widely distributed in the brain with the highest concentrations found in the olfactory bulb, hippocampus, cerebral cortex, and the arcuate nucleus within the hypothalamus."
• Insulin serves to move glucose into the cell for use and it seems to inhibit appetite, too.

[edit] Pancreatic polypeptide

• "Pancreatic polypeptide (PP) is released from cells found at the periphery of pancreatic islets, again in proportion to the amount of calories ingested with the effect of inhibiting gastric emptying."

[edit] Other sites

• Gluccocorticoids from the adrenal glands can affect appetite.
• Steroid hormones from the gonads can affect appetite.
• Thyroid T3 increases appetite but also increase basal metabolic rates.
• Hepatocyte derived factors also seem to help regulate other factors like leptin and adiposity.

[edit] Summary

• The evidence suggests that leptin signaling is the primary mechanism of appetite control and that there is little redundancy in the pathway.
• The evidence regarding gut-derived, appetite-affecting factors suggests that they act in balance with one another and with much redundancy to slightly affect appetite and to coordinate GI tract function and food intake.
• We still have lots to learn.