2. Neuroendocrine Regulation of Energy Storage & Utilization Neuroendocrine Regulation of Energy Storage & Utilization By Dr. Khaled Ibrahim By

3.  Describe neuroendocrine regulation of energy metabolism during the fed state  Discuss regulation of energy metabolism during the fasted state.  List the counter-regulatory hormones and describe their effects.  Discuss the Maintenance of Long-Term Energy Balance & Fat Storage  Correlate this knowledge to the related clinical conditions. By the end of this session, the student should:

4.  Throughout the day; 2 phases alternate regarding regulation of energy It is anabolic metabolism, during which energy is stored in the form of energy-rich compounds (e.g., ATP) The fed state The fasted state It is catabolic phase during which endogenous energy sources are utilized  Both phases alternate to: 1- preserve adequate glucose supply to the brain. 2- maintain body functions (as thermoregulation, food digestion, and physical activity.  Both phases alternate to: 1- preserve adequate glucose supply to the brain. 2- maintain body functions (as thermoregulation, food digestion, and physical activity.

5. during the Fed State: Following a meal (postprandial state) Glucose ↑insulin release -- ---> a) ↑ glucose uptake in muscle, fat, and liver. b) ↓ hepatic glucose output; and c) ↑ glycogen synthesis. The majority of insulin-stimulated glucose taken up is stored as glycogen. Fat Most of the body's energy reserve is stored in adipose tissue in the form of triglycerides. The principal hormone involved in this lipogenic response is insulin, through activation of lipogenic and glycolytic enzymes. Protein insulin inhibits proteolysis. IGF-I stimulates protein synthesis. GH and testosterone are of particular importance during growth & development, as well as during adulthood and senescence. Thyroid hormones are required for normal growth & development. They stimulate bone growth indirectly by increasing secretion of GH and IGF-I and directly by activating gene transcription.

7.  Any deviation from the basal condition, such as changes in body temperature (fever or hypothermia), the level of activity of the individual (exercise or sleeping), or time from the last meal (fed or fasted), will affect the metabolic rate (needs more energy). During the Fasting State  The total amount of energy produced per unit of time by a given individual = the metabolic rate. basal metabolic rate (BMR).  The amount of energy expended by an awake, resting (mentally and physically) individual, 12–14 hours following the last meal, at normal (or thermoneutral) body temperature is called the basal metabolic rate (BMR).  The BMR is the amount of energy required to maintain breathing, brain activity, enzymatic activity, and other functions without any physical movement of the individual.

8. Glucose peripheral glucose utilization hepatic glucose production As hepatic glycogen stores are depleted during a period of prolonged fasting (approximately 60 hours ) hepatic gluconeogenesis predominates hepatic glucose output is derived from the breakdown of hepatic glycogen stores (a maximum of 70–80 g in humans)

9. Fat Muscle for energy product ion Liver substrates for gluconeogen esis (glycerol) lipoprotein synthesis (free fatty acids) Brain cannot utilize fatty acids for energy when blood glucose levels become compromised. In this case, ketone bodies provide the brain with an alternative source of energy, amounting to nearly two thirds of the brain's energy needs during periods of prolonged fasting. During fasting, plasma insulin levels ↓ and plasma GH and glucagon both ↑. As the fasting period progresses) or increased energy demand (as with strenuous exercise), catecholamines ↑ and play an important role in the stimulation of lipolysis ------> conversion of triglycerides into FFA + glycerol that are released to:

10.  The effects of Prolonged changes in either the protein synthetic or degradative processes (or both) leading to loss of lean body mass have been shown to increase morbidity and mortality from several diseases, including cancer and AIDS. Protein  there is no storage pool for body protein. Therefore, under fasting conditions, essential proteins are catabolized. some of which can be utilized for gluconeogenesis. 1 glucagon predominantly increases hepatic uptake of amino acids. 2 Epinephrine increases production of the gluconeogenic amino acid alanine by muscle and its uptake by the splanchnic bed. 3 Cortisol favors muscle protein breakdown and hepatic amino acid uptake

11. Counter-regulatory Hormones Glucagon Growth Hormone CortisolEpinephrine N.B.: GH and cortisol facilitate glucose production and limit glucose utilization, but neither of them plays a critical role. Their effects are not immediate (delayed for about 6 hours); thus, they are mostly involved in defense against prolonged hypoglycemia.

13. Maintenance of Long-Term Energy Balance Two hormones that have been identified as crucial in the long-term regulation of energy balance are insulin and leptin. Both hormones are released in proportion to body fat. They are transported into the brain, where they modulate the expression of hypothalamic neuro-peptides known to regulate feeding behavior and body weight, resulting in inhibition of food intake and increase in energy expenditure.

14. These areas relay: 1)many neural and hormonal signals from the gastrointestinal tract. 2)Mechanical stretch receptors sense stretch of the stomach and other areas of the intestine. 3)Taste information. 4)Other signals regarding smell, sight, memory of food, and the social context under which it is ingested are also integrated These areas relay: 1)many neural and hormonal signals from the gastrointestinal tract. 2)Mechanical stretch receptors sense stretch of the stomach and other areas of the intestine. 3)Taste information. 4)Other signals regarding smell, sight, memory of food, and the social context under which it is ingested are also integrated Hypothalamic Integration The hypothalamus receives innervation from several areas, notably the nucleus tractus solitarius and area postrema in the brainstem.

15. Integration of these signals results in the activation of gene expression of mediators implicated in the regulation of satiety and development of obesity. These genes control thermogenesis (uncoupling proteins), hormone synthesis (ghrelin, leptin, and cholecystokinin and adiponectin), and neurotransmitter (neuropeptide Y) availability Integration of these signals results in the activation of gene expression of mediators implicated in the regulation of satiety and development of obesity. These genes control thermogenesis (uncoupling proteins), hormone synthesis (ghrelin, leptin, and cholecystokinin and adiponectin), and neurotransmitter (neuropeptide Y) availability

18.  The specific effects of leptin on fat metabolism are as follows: o Decrease in fat storage. o Increase in sympathetic-mediated energy expenditure. o Increase in expression of uncoupling proteins. o Decrease in triglyceride content by increasing fatty acid oxidation. o Decrease in activity and expression of esterification and lipogenic enzymes. o Decrease in lipogenic activity of insulin, favoring lipolysis.  The specific effects of leptin on fat metabolism are as follows: o Decrease in fat storage. o Increase in sympathetic-mediated energy expenditure. o Increase in expression of uncoupling proteins. o Decrease in triglyceride content by increasing fatty acid oxidation. o Decrease in activity and expression of esterification and lipogenic enzymes. o Decrease in lipogenic activity of insulin, favoring lipolysis.  It is a peptide hormone (146 amino acids) thought to serve as an indicator (lipostat) of energy stores, as well as a modulator of energy balance. LeptinLeptin

20. The overall effect of leptin is to deplete fat stores and promote leanness in a feedback regulatory system. In this feedback loop, leptin produced by adipose tissue functions as a sensor that monitors the level of energy stores (adipose tissue mass). The signal is received and integrated by hypothalamic neurons, and an effector response, most likely involving: 1)modulation of appetite centers (↓ food intake) and 2)sympathetic nervous system activity (↑ energy expenditure). The overall effect of leptin is to deplete fat stores and promote leanness in a feedback regulatory system. In this feedback loop, leptin produced by adipose tissue functions as a sensor that monitors the level of energy stores (adipose tissue mass). The signal is received and integrated by hypothalamic neurons, and an effector response, most likely involving: 1)modulation of appetite centers (↓ food intake) and 2)sympathetic nervous system activity (↑ energy expenditure).  Leptin secretion exhibits a circadian rhythm, with a nocturnal rise over daytime secretion. Leptin plasma concentrations are low at about noon and begin to rise toward 3 PM; they reach maximal values during the night.  These changes in leptin plasma concentrations are not influenced by meal ingestion and meal-induced increases in the circulating insulin concentration.  Leptin secretion exhibits a circadian rhythm, with a nocturnal rise over daytime secretion. Leptin plasma concentrations are low at about noon and begin to rise toward 3 PM; they reach maximal values during the night.  These changes in leptin plasma concentrations are not influenced by meal ingestion and meal-induced increases in the circulating insulin concentration.