Leptin: Food intake, Energy balance, and Endocrine Function By: Dina M, Trabzuni Advisor; Prof. Hamza Abu-Tarboush 698 FSN

Introduction 698 FSN Leptin was discovered in Derived its name from leptos (thin). Leptin is a hormone consist of 167 A. A. Leptin regulate body energy homeostasis, food intake, storage and expenditure, fertility and immune functions.

Secretion Leptin secreted mainly from white adipose tissue (WAT) Energy balance regulate the production of leptin. Secreted in lower level from other tissues, such as placental and fetal tissues, mammary gland, stomach, muscle, brown adipose tissue,… et in rodent and human species Regulation

By contrast, leptin production is inhibited when energy stores are depleted. When energy stores are replete, leptin production is high. Figure(1): regulation of leptin secretion

Leptin receptors (LR) LR isoforms can be divided into: Secreted form ( Bind circulating leptin). Short form (has a peripheral action ). Long form (LR), is responsible for the central action of leptin.

Appetite and satiety 1. Appetite and Satiety: NPY Leptin has been shown to suppress NPY release from the hypothalamus. Inadequate nutrition delays or prevents the onset of puberty 2. Regulation of reproduction Inadequate nutrition delays or prevents the onset of puberty Leptin Puberty Leptin – Central effect

Autonomic Nervous System 1. Autonomic Nervous System Leptin Sypathatic nerve activity In brown adipose tissue (BAT) 2. Growth Leptin acts as a skeletal growth factor with a direct peripheral effect on growth centers. Bin-Ari et al (2002) work demonstrated the reversal of the caloric restriction effect and continued growth of skeletal bone in mice treated with Leptin. Leptin – peripheral effect

Figure(2): Effect of leptin on the physiological processess (Bates & Myers, 2003).

LeptinLeptin in Regulating Neuroendocrine function in Humans leptin accelerates GnRH – pulsatility in arcute hypothalamic neurons regulating the release of ganadotropin. Leptin acts as a permissive signal to activate the reproductive axis. 1. Hypothalamic- Pituitary – gonadal axis: Direct effect ( leptin and leptin receptors are expressed in pituitary cells

2. Hypothalamic – pituitary - thyroid axis: Starvation T 3 - T 4 Leptin Figure(3): Regulation of neuroendocrine function by leptin (Blüher &Montozors, 2004)

Leptin and the regulation of Energy balance Synthesis of TG ====== Utilized TG Leptin- deficient children show ravenous feeding behavior and develop extreme obesity, this support that leptin plays an important role in satiety. Ob gene Leptin Administration of leptin Food intake Reverse the weight gain in obese models.

Exogenous leptin may be relatively more effective in subjects in whom endogenous leptin production has first been reduced by dieting. Individuals vary in : The ability of exogenously administered leptin to gain access to the CNS. impairment in the transport of exogenous leptin into the CNS when leptin concentrations are elevated (Leptin resistance).

The “Satiety Center”, are crucial site of leptin action ( DMH, ARC, VHM ) LRb mRNA is expressed highly in the ARC, where it is found in two salient populations of neurons NPY AgRP Orexigenic (appetite-stimulating) POMC  MSH Anorectic (appetite-suppressing)

Figure4: Anorectic and Orexigenic affect of leptin

Leptin inhibit NPY/AgRb neurons via LRb, and suppress expression of these neuropeptides. LRb signaling stimulates the production of orexigenic peptides. The concentration of plasma leptin and leptin mRNA level in adipocytes change rapidly and reflect the energy balance changes associated with fasting and refeeding Refeeding leptin RMR Low energy intake PreventRMR

Insulin plays an important role with permissive concentration of cortisol. Figure (4): Regulation of Leptin production in Humans (Fried et al, 2000)

Metabolic effects of leptin on leanness independent of food intake 1. increase energy expenditure : Leptin Ins., CORT., GH, NE, E, T 3, T 4 Leptin CNS, endocrine gland. Leptin AT lipolysis AT/ Liver Lipogenesis Insulin sensitivity Glucose utilization,FA oxidation (in muscle).

2. In-place utilization of fat: Leptin acts on CNS TG lipolysis in AT Export FFA to Liver Keton bodies

3. Thermogenesis : Leptin BAT, WAT, Muscle, Liver UCP synthesis SNS innervations Body heat

Effect of specific nutrients on Leptin level Meal composition and intake of specific nutrients might affect leptin expression. Nutritional status can influence serum Leptin over the short time, independent of adiposity. In high-fat fed animals, saturation or a defect of the leptin transport system across the blood-brain barrier may contribute to the leptin resistance n-3 PUFA reduce adipose leptin expression in cell model by reducing the transcription factors PPARγ and SREB-1.

Level of dietary protein can effect leptin level. Rats fed low protein diets Hyperphagia high fructose diet has an intensive effect on plasma leptin level which is induced by excessive insulin secretion. Body Fat increased

Retinoids down-regulate leptin expression on BAT and WAT depots and circulating leptin levels. Retinoids does not increase food intake because it suppress expression NPY and its receptors. Retinoids stimulate the expression of UCPs. Reduce circulating levels of leptin, so more hunger and less energy expenditure.

Conclusion Figure (5): Summary model of leptin affecting central nervous effectors pathway (Dijk, 2001).