FOOD INTAKE AND ENERGY EXPENDITURE ARE CONTROLLED BY COMPLEX, AND DISTRIBUTED NEUROENDOCRINE SYSTEMS THAT ESTABLISH ENERGY BALANCE. MOST VERTEBRATES CAN STORE A CONSIDERABLE AMOUNT OF ENERGY AS FAT IN THEIR ADIPOCYTES FOR LATER USE. SO, A PREDISPOSITION TO OBESITY CAN RESULT FROM ANY PATHOLOGICAL MALFUNCTION OR LACK OF ADAPTATION TO CHANGING ENVIRONMENTS OF THIS HIGHLY COMPLEX SYSTEM. MANIPULATING ELEMENTS OF THIS REGULATORY SYSTEM, NAMELY THE BRAIN AND THE HORMONAL SIGNALS FROM MIGHT PROVIDE THE BEST OPPORTUNITY FOR US TO COMBAT OBESITY. THE HYPOTHALAMUS AND THE BRAINSTEM ARE THE MAIN BRAIN REGIONS RESPONSIBLE FOR THE REGULATION OF ENERGY HOMEOSTASIS AND AREAS IN THE CORTEX AND LIMBIC SYSTEM ARE IMPORTANT FOR PROCESSING INFORMATION REGARDING PRIOR EXPERIENCE WITH FOOD, REWARD, AND EMOTION, AS WELL AS SOCIAL AND ENVIRONMENTAL CONTEXT. SOME OBESITY THERAPIES TARGET CENTRAL NEUROTRANSMITTERS IN ORDER TO REDUCE BODY WEIGHT. THE HYPOTHALAMUS AND BRAINSTEM RECEIVE NEURAL AND HORMONAL SIGNALS FROM THE PERIPHERY (INCLUDES LEPTIN, ADINOPECTIN AND RESISTIN SECRETED BY THE ADIPOCYTES AND THE PANCREATIC INSULIN) THAT ENCODE INFORMATION ABOUT ACUTE NUTRITIONAL STATE AND ADIPOSITY.INSULIN AND LEPTIN SHARE MANY PROPERTIES AS ADIPOSITY SIGNALS AND THEIR CIRCULATING CONCENTRATIONS ARE PROPORTIONAL TO ADIPOSITY. LEPTIN AND INSULIN ALSO CROSS THE BLOOD-BRAIN BARRIER AND INTERACT WITH SPECIFIC RECEPTORS IN THE HYPOTHALAMUS. MOREOVER, THROUGH INTERACTION WITH SPECIFIC NEURONS IN THE HYPOTHALAMUS, THEY REDUCE FOOD INTAKE AND BODY WEIGHT. OBESITY IS CHARACTERIZED BY HIGHER CIRCULATING LEVELS OF INSULIN AND LEPTIN AND A DEVELOPMENT OF RESISTANCE TO THESE HORMONES. ADIPONECTIN, AND RESISTIN ARE REPORTED TO ENHANCE OR IMPAIR INSULIN SENSITIVITY, RESPECTIVELY. APART FROM THE ABOVE MECHANISMS, NEURAL AND ENDOCRINE SIGNALLING FROM THE GUT IS BELIEVED TO HAVE IMPORTANT ROLES IN THE SHORT-TERM REGULATION OF appetite BY MEDIATING FEELINGS OF HUNGER AND SATIETY. GUT HORMONES LIKE CHOLECYSTOKININ, AMYLIN, PEPTIDE YY (PYY), PANCREATIC POLYPEPTIDE, GLP-1, GLP-2, AND OXYNTOMODULIN ACT AS ANORECTIC SIGNALS THAT REDUCE FOOD INTAKE. GHRELIN OFTEN REFERRED TO AS THE.’HUNGER HORMONE’ PRODUCES AN OREXIGENIC SIGNAL AND INCREASES appetite. THE GUT HORMONE GENES ARE WIDELY EXPRESSED, NOT ONLY IN ENDOCRINE CELLS, BUT ALSO IN CENTRAL AND PERIPHERAL NEURONS AND CERTAIN TUMOUR CELLS. THESE PEPTIDES THUS ACT AS TRUE BLOOD-BORNE HORMONES AS WELL AS LOCAL GROWTH FACTORS. FOR MANY GUT HORMONES, THE PRECISE MECHANISMS OF CENTRAL ACTION ARE UNKNOWN. A NUMBER OF GUT HORMONES ALSO ACT AS NEUROTRANSMITTERS IN THE BRAIN, WHERE THEY DO NOT NECESSARILY SERVE THE SAME FUNCTIONS AS IN THE PERIPHERY, MAKING IT DIFFICULT TO PINPOINT THEIR ENDOCRINE EFFECTS. GUT HORMONES HAVE A NUMBER OF FUNCTIONS, INCLUDING THE REGULATION OF BLOOD GLUCOSE LEVELS, GASTROINTESTINAL MOTILITY AND GROWTH, EXOCRINE SECRETION AND ADIPOCYTE FUNCTION. MOST OF THESE HORMONES ARE SENSITIVE TO GUT NUTRIENT CONTENT. THE APPLICATION OF A RESTRICTED ENERGY AND WEIGHT REDUCING DIET IS BASED ON SOME OF THE PRINCIPLES OF THIS INTERPLAY OF GUT HORMONES. TODAY WE RECOGNIZE MORE THAN 30 PEPTIDE HORMONE GENES, EXPRESSING MORE THAN 100 BIOACTIVE PEPTIDES, AND OTHER HORMONAL FACTS TRULY MAKE THE GUT THE LARGEST ENDOCRINE ORGAN IN THE BODY. GUT HORMONES MAY REPRESENT USEFUL TARGETS FOR FUTURE OBESITY THERAPIES AS THEY CAN ACTIVATE CIRCUITS IN THE HYPOTHALAMUS AND BRAINSTEM FOR THE REGULATION OF ENERGY HOMEOSTASIS. SO AS CLAIMED BY MURPHY AND BLOOM (2006) IT MAY BE SAID THAT, “GUT HORMONES MAY YET PROVE THAT THE WAY TO A MAN. S BRAIN IS THROUGH HIS STOMACH”.