ABSTRACT
Glucagon-Like Peptide-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 From Proglucagon Gene to GLP-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 GLP-1 Producing L-Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 Regulation of GLP-1 Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Nutrients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Neurohormonal Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
GLP-1 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Physiological Effects of GLP-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Pancreatic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Extrapancreatic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 Hepatoportal Vein and GLP-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 GLP-1 Analogs and Inhibitors of DPP-IV in the
Treatment of Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . 236 Other Gastrointestinal Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
8171: “chap11” — 2007/12/3 — 18:10 — page 220 — #2
of
In the majority of adults, the qualitative and quantitative composition of food intake varies considerably from meal to meal and from day to day, while adiposity and body weight are remarkably constant despite huge short-term variations in energy balance. Most individuals match cumulative energy intake to energy expenditure with great precision whenmeasured within a period including several meals.1 Such an active process-energy homeostasis-allows stability in the amount of body energy stored as fat. The hypothalamus was first identified more than 50 years ago as “cent-
ral” in the energy homeostatic process. Brain lesion and stimulation studies, published some six decades ago described the hypothalamus as a major center controlling food intake and body weight, with the ventromedial nucleus (VMH) as a “satiety centre,” and the lateral hypothalamic nucleus (LHA) as a “hunger centre.”2 However, central regulation of satiety requires that the brain integrates energy content of the body. Hence, the brain is connected to peripheral body weight sensor systems. Nutrients, hormones, and neuromediators are regulators of food intake directly triggering the brain. However, such messages must originate from cells, which are aware of the energy stores. Since 1995, the most studied related mechanism has been the leptin system.3 This hormone, produced by the adipose tissue, is considered as a “lipostat” since it is produced proportionally to the fat mass and has a remarkable capacity to reduce food intake. Therefore, the adipose tissue is no longer considered as a fat storage organ but refers to the brain of the energy stores by themeanof hormones such as leptin. Similar to the reasoning that fat mass is the most obvious tissue informing the brain about the energy stores, the gastrointestinal tract (GI) is the most obvious organ to inform the brain of energy intake by a mechanism called “energystat.” Therefore, the GI secretes sufficient peptide-hormones able to control food intake and energy homeostasis. Consequently, an impaired regulation of the lipostat and energystat will prevent the brain from the messages required for the regulation of energy homeostasis andwill lead tometabolic diseases such as obesity, diabetes, or cachexia. Wewill review themajor regulators of satiety and glucose homeostasis (Figure 11.1); afterward, we will focus on the peripheral gut hormones-brain axis and its relevance to appetite control.
