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Body weight Homeostasis SD (1).pdf

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2025-05-05 1 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY BODY WEIGHT HOMEOSTASIS PROFESSOR SUZANNE L DICKSON | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 1 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Measuring obesity and obesity statistics | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 2

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2025-05-05 2 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY DEFINITIONS Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. ADULTS: A body mass index (BMI) over 25 is considered overweight and over 30 is obese. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON

18.5 18.5-24.9
25.0-29.9 30.0-34.9 35.0
BODY MASS INDEX (kg/m2) 3 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Body mass index (BMI) = weight/height2 (kg/m2) Weight (kg) Height (m) BMI Normal 20-25 Overweight 25 Obese 30 Morbidly Obese 40 BMI for adults | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 4

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2025-05-05 3 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Weight (kg) Height (m) BMI Normal 20-25 Overweight

25 Obese 30 Morbidly Obese 40 Weight: 110 Kg Height: 1.8 m à BMI: 34 A cautionary note ….. This calculation does not predict obesity for body builders (muscle) or for those that are very tall | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 5 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Age 5-19: Use BMI-for-age Overweight : >1 standard deviation above the growth reference mean Obesity: >2 standard deviations above the growth reference mean Age 5 19 yrs | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON BMI-for-Age GIRLS obese overweight BMI (Kg/m2) 6

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2025-05-05 4 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Age <5 Use Weight-for-age Overweight: >2 standard deviations above the growth reference mean Obesity: >3 standard deviations above the growth reference mean Age Birth 5 yrs | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Weight (kg) Weight-for-Age GIRLS 7 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Direct methods for assessing fat mass Underwater weighing Accurate. Was gold standard before more advanced methods. Fat vs non-fat tissue have different densities. Whole-Body (ADP) Air Displacement Plethysmography Like underwater weighing – displace air instead of water. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Total body water (TBW). Drink deuterated (or tritiated) water à ends up in the fat-free compartment à sampling gives TBW. From this, fat mass can be calculated (since body weight is known). 2H2O H2O 2H2O H2O + 5 hours e.g. 1 liter e.g. 80 liters Dilution: 1:80 Sample (eg saliva) (known) (unknown) 8

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2025-05-05 5 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Direct methods for assessing fat mass Dual X-Ray absorptiometry (DEXA) X-rays of two different energies. One absorbed more strongly by fat.
Subtract one image from the other à amount of fat relative to other tissues at each point. Measures total fat and gives distribution. €€€. Involves exposure to (low level) radiation. OFTEN USED IN RESEARCH. Computerized tomography Cross-sectional radiographs of abdomen à computerized measurement of total fat area and regional fat determination (e.g. subcutaneous versus visceral fat). €€€. Radiation (like many x-rays). Bioelectrical impedance Resistance between 2 electrodes is higher in obese individuals. Resistance high for fat & low for water. Not accurate. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 9 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Indirect methods for assessing fat mass ØSkinfold measurements – subcutaneous fat measured using calipers. Use conversion tables to estimate body fat % to about 3-5% accuracy. More useful than BMI in athletes. ØWaist:hip ratio – cut-offs are ≥ 0.90 cm in men and ≥ 0.85 cm in women ØBMI - based on weight and height (kg/m2) Most obesity statistics are based on BMI data | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Source: hereandnowwellness.com 10

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2025-05-05 6 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 2020: % US adults with an obese BMI (>30) 11 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY 1992 2000 2010 Sweden – Prevalence of Overweight (%) % BMI>25 kg/m2 <18

18-25 25-35 35 And in 2022 Adults – 35% overweight, 16% obese Children – 20% overweight. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON DOI:10.1177/1403494815579478 12

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2025-05-05 7 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Health consequences of obesity OBESITY CARDIOVASCULAR DISEASE TYPE 2 DIABETES Increased risk: Breast cancer Bowel cancer Osteoporosis Lung disease Strokes Heart attacks | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 13 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Metabolic Syndrome A cluster of conditions that occur together, increasing risk of heart disease, stroke and type 2 diabetes. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON About two-thirds of people suffering from obesity develop metabolic syndrome. 14

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2025-05-05 8 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Metabolic Syndrome Diagnosis (WHO 1998) Type 2 diabetes plus 2 out of 3 of the other components: Type 2 diabetes: ­ Fasting glucose (> 6.5 mmol/L) ¯ Glucose tolerance or ­ Insulin resistance High Blood Pressure Visceral Obesity Blood fat disturbance: ­ Triglycerides ¯ HDL (good) cholesterol ­ LDL (bad cholesterol) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 15 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Debate regarding metabolic syndrome We say that “it is just a constellation of symptoms or sub- diseases” We disagree. Surely there is a causal relation between symptoms – perhaps even a common cause? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Depositphotos 16

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2025-05-05 9 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Below waist Above waist Increased risk of metabolic disturbances ­ Visceral fat à ­ Free Fatty Acid (FFA) release , e.g. to the liver (bad) à ­ release of adipokines* (exception is adiponectin, whose secretion is decreased). *Adipokines are fat-derived cytokines such as leptin and resistin and also immune-stimulating hormones e.g. interleukin-6 (IL-6), TNFa § Android § Central § Abdominal § Truncal § Upper body § Gynoid § Peripheral § Gluteo-femoral § Lower body | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 17 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY How does obesity cause insulin resistance?

  1. Free fatty acid ”overflow hypothesis”
  2. Adipokines, immune stimulating hormones from white adipose tissue (↑ TNFa, ↑ resistin, ↓adiponectin) Both can be true! | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 18

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2025-05-05 10 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucose Glucose Glucose Glucose Health Disease

  1. Fat overflow hypothesis. Fat outside fat tissue is dangerous for metabolic health | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 19 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
  2. “Adipokine” hypothesis Immune stimulating hormones (adipokines) from adipocytes and macrophages in fat à inflammationà diabetes in liver, muscle and pancreas Adipocyte Macrophage Blood vessel Glucose Glucose Healthy Metabolic syndrome adipokines Insulin Insulin IL-1β | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 20

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2025-05-05 11 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The relation between obesity, adipokines and their impact on insulin resistance ↑ TNFα ↑ resistin ↓ adiponectin ↑ leptin INSULIN RESISTANCE + _ Leptin resistance Adipokines | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 21 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Adipokines in metabolic syndrome | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Adiponectin – Levels reduced in metabolic syndrome. In normal weight individuals, it has beneficial effects (increases insulin sensitivity, anti- inflammatory, anti-artherosclerosis).

  1. modify insulin sensitivity e.g. acylation stimulating protein, tumor necrosis factor α (TNF-α), IL-6, resistin, visfatin, apelin, omentin, chemerin, leptin and adiponectin. TNFa & IL6 - Levels increased in metabolic syndrome. Proinflammatory. Produced by adipocytes and macrophages. Cause insulin resistance and increase circulating free fatty acids. Adipokines include proteins that:
  2. impact on vascularity e.g. angiotensinogen, plasminogen inhibitor protein, PAI-1) among others.
  3. ↓ insulin release (e.g. IL-1β) 22

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2025-05-05 12 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Adipokines in metabolic syndrome | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Role in many metabolic processes: Energy expenditure, neuroendocrine function, immune function, vascular remodelling, angiogenesis, fatty acid oxidation, lipogenesis, gluconeogenesis, glucose uptake, insulin signalling, and energy expenditure in metabolically active tissues such as the liver, skeletal muscle and the brain. Site of action: Can act locally, through autocrine/paracrine mechanisms, or systemically, through endocrine effects I’m not expecting you to memorize this list but to realise they have many & diverse functions 23 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY ↔Cortisol (despite signs of ↑ cortisol activity - looks like Cushings syndrome!) ↑ androgens in women (polycystic ovarian syndrome, PCOS) ↓ androgens in men ↓ growth hormone Additional endocrine changes in metabolic syndrome | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 24

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2025-05-05 13 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Body weight homeostasis | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON

  • Powerful physiological processes aim to keep body weight constant 25 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Energy Expenditure:
  • Basal Metabolism
  • Physical activity
  • Adaptive thermogenesis** Food intake & energy expenditure balanced à body weight maintained at a “set point”.
  1. Genetic predisposition*
  2. Long term changes in body weight
  3. Obesogenic environment *Predisposition= tendency to suffer from **Occurs in brown adipose tissue. Factors influencing the “set point” Ø Target weight maintained with an extraordinary degree of control. Ø “Set point” controller = brain (especially hypothalamus) “Set point” hypothesis of body weight regulation | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 26

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2025-05-05 14 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY In obesity, there is a defense of an elevated body weight, rather than the absence of regulation. Evidence that we defend our body weight at a set point? ØBody weight defended despite diet attempts (­ hunger & ¯ metabolism). ØDiet and lifestyle changes ineffective.
ØReturn to “set point” (normal weight) after dieting or illness and after voluntary overfeeding. ØThe 0.5 kg gained per year during ageing (average) = surprisingly little “Set point” is a hypothesis to explain obesity!!! | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Age: 20 50

  • 30 kg 27 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Weight gain as we age | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Age 20 Age 50
  • 15 kg Powerful Physiological Systems Control Energy Balance & Body Weight. 1 g fat = 9 kcal 15 kg fat = 130,000 kcal 13,000 kcal in 30 years = 86 kcal/week 8 minutes running or Per week imbalance: 28

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2025-05-05 15 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Change in weight (kg) Overfeeding (6736 kcal/day) months Body weight Fast mass Pasquet P, Apfelbaum, M. Am J of Clin Nut 1994;60:861-3 “Guru Walla" fattening session in the Massas ethnic group in Northern Cameroon "The fattening session resulted in a mean extra energy intake of 955 MJ and an increase of 17kg in body weight...Over the whole overfeeding session, we noted a 43.5% mean increase of resting metabolic rate, which is much higher than previously reported” Evidence for set point: Return to normal weight after a period of voluntary over-feeding | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 29 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Does energy expenditure adjust if we over- or under-eat enough calories to alter our body weight? Over-eat à gain 10% body weight Diet à Lose 10% or 20% body weight Measure Energy Expenditure Predict Energy Expenditure Difference?? Leibel RL et al. N Engl J Med 1995;332:621-628. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 30

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2025-05-05 16 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Does energy expenditure adjust if we over- or under-eat enough calories to alter our body weight? Leibel RL et al. N Engl J Med 1995;332:621-628. Over-eating (à weight gain) à ­ Energy expenditure (> 500 kcal above that predicted) Food restriction (à weight loss) à ¯ Energy expenditure (¯ was > 300 kcal more than predicted) Observed minus predicted total energy expenditure (kcal) Dieter’s curse People go up in energy expenditure when they gain weight & down in energy expenditure when they lose it – more than expected! | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 31 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Body weight Set point Free choice Free choice Free choice Under Feed Over feed ¯ energy expenditure ­ appetite ­ energy expenditure ¯ appetite (less effective) Both under- and over-nutrition can lead to weight gain over time | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 32

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2025-05-05 17 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Food available EAT!!!! STORE ENERGY (TO PREPARE FOR FUTURE FAMINE) ­­ HUNGER à search for food ¯ METABOLISM à save energy survival LEAN ENVIRONMENT Food scarce (famine) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON THEN….. In our evolution, there was genetic pressure to increase body weight 33 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY EAT!!!! STORE ENERGY (TO PREPARE FOR FUTURE FAMINE) OBESOGENIC
ENVIRONMENT ­­ HUNGER à search for food ¯ METABOLISM à save energy Food available 24/7 Dieting (attempts to limit weight gain) Obesity Same genetic pressures as our ancestors | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON NOW: Food is more available … but our genetics have evolved to increase our body weight EssayPlant.com 34

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2025-05-05 18 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Energy expenditure Basal Metabolism Physical activity Adaptive thermogenesis Metabolism Energy Storage (fat) Total energy expenditure (= Heat+work done on environment)* *When at rest, all energy expenditure is equal to heat produced (ie thermogenesis) •Variable (at most 10% in modern life) •Regulated by brain •Responds to temperature & food intake •Occurs in brown adipocyte mitochondria, skeletal muscle & other sites •Variable (~25%) (~65%) For performance of cellular & organ functions: •synthetic processes •electrical work •membrane transport •detoxification •degredation Energy intake (Food) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 35 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Energy dissipated (wasted) in the form of heat in response to environmental changes, essentially cold exposure and food intake. It helps protect against weight gain by causing a compensatory increase in energy expenditure when we eat.
Adaptive thermogenesis | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 36

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2025-05-05 19 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Function = energy expenditure (not storage). Present in interscapular area.
Present in human infants but declines with age. Sympathetic nervous system (SNS) increases BAT activity in response to cold or increased food ingestion. Adaptive thermogenesis. Heat generated in mitochondria via “uncoupling”. Electron transport chain MITOCHONDRIA Fatty acids & glucose H+ ATP synthase H+ ADP ATP (Energy storage) UCP1 H+ H+ UCP1=uncoupling protein 1 It is present in BAT but not in other cells. It is increased by over- eating and decreases with fasting HEAT | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Brown Adipose Tissue (BAT) 37 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY PET scan after intravenous injection of 18F- fluorodeoxyglucose (18F-FDG) à BAT visualized New information on BAT: Present in human adults. Women have more than men. More in younger adults More BAT in lean subjects? Therapeutic interest? Stimulation of BAT à energy expenditure & weight loss | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 2010: BAT also discovered to be present in human adults DOI:10.1038/ijo.2010.241 38

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2025-05-05 20 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY 2. Thyroid hormones (TRβ on BAT) - chronic ­ UCP-1 expression in BAT (BUT NOTE: THEY ARE ALSO THE PRIMARY CONTROLLER OF THE BASAL METABOLIC RATE; ACTING ON MOST BODY CELLS (NOT BRAIN) TO ­ ­ ENEGY EXPENDITURE)

  1. Noradrenaline (β3 AR on BAT) – acute Caused by sympathetic nervous system (SNS) activation. Contribute to heat produced when emotionally stressed. ­ Metabolism of brown adipose tissue (BAT). ­ UCP1 activation and hence energy expenditure
  2. Glucocorticoids (via glucocorticoid receptor on BAT) Inhibitory effect on BAT. Suppresses noradrenaline-induced UCP1 activation
  3. Leptin (via ObRB in hypothalamus that stimulate SNS) ­ UCP-1 expression in BAT Hormones important for BAT activation | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 39 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY BMI Energy expenditure Obese Ex-obese (↓ diet-induced thermogenesis, eg ↓ T3) Lean A formerly obese individual will require ~300–400 fewer calories per day to maintain the same body weight and physical activity level as a never-obese individual of the same body weight. Reduced energy expenditure in the post-obese state | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 40

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2025-05-05 21 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Body weight Homeostasis - the control systems | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 41 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Effector systems Sensors Altered Internal Environment Principles of homeostasis – keeping (body weight) constant | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Controller Homeostasis

  • maintaining a steady state.
  • involved feedback systems. 42

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2025-05-05 22 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Food intake Energy expenditure Adaptive thermogenesis Sensors ??? Energy deficit/excess Key questions:

  1. What are the control systems in the brain that alter food intake & energy expenditure?
  2. What are the sensors?
  3. Why do these fail in ways that result in body weight gain & obesity? Hunger/full etc Longterm Short term Principles of homeostasis – keeping (body weight) constant | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 43 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Locke et al Nature. 2015 Feb 12;518(7538):197-206 Genes linked to BMI are mostly found in brain, and notably in the hypothalamus Energy homeostasis control system is in brain | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 44

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2025-05-05 23 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Brain areas involved in energy balance regulation | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Hypothalamic and brainstem autonomic circuitry (orange) includes the arcuate nucleus (ARC), the dorsomedial hypothalamus (DMH), the dorsal-vagal complex (DVC), the lateral hypothalamus (LH), the pontine parabrachial nucleus (PBN), the preoptic area (POA), the paraventricular hypothalamus (PVH), the raphe pallidus (RPa), and the ventromedial hypothalamus (VMH). Structures of the brain executive system (green) include the anterior cingulate cortex (ACC), the insula (Ins.), and the prefrontal cortex (PFC). Structures of the brain reward system (blue) include the amygdala (Amy.), hippocampus (Hipp.), Ins., LH, nucleus accumbens (NAc), striatum (Stri.), and ventral tegmental area (VTA). DOI:10.1111/nyas.13263 45 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY §Nearly all hypothalamic nuclei engaged. §Especially - Mediobasal hypothalamus (MBH) - includes arcuate nucleus (Arc) and ventromedial nucleus (VMN) – energy intake and adaptive thermogenesis. §Arc cells project to many other hypothalamic (and extra- hypothalamic) areas to regulate energy balance. §Lateral hypothalamus – feeding center. Autonomic control of energy balance: Hypothalamus | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON VMH, LH, DMH, POA Arc PVH Appetitice & Consummatory Behaviours Adaptive thermogenesis Autonomic & neuroendocrine control of food intake & energy expenditure Hypothalamic areas regulating energy balance.

  • VMN 48

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2025-05-05 24 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY

  1. Lesions of key hypothalamic areas cause animals to lose control of their set point for body weight. Ventromedial nucleus (VMN) lesion à obesity.
    Role = satiety center Lateral Hypothalamus (LH) lesion à appetite loss. Role= hunger center
  2. Arcuate nucleus (Arc): Contains orexigenic AgRP/NPY neurones and anorexigenic POMC neurones.
  3. Leptin Fat-derived hormone that suppresses food intake. Activates POMC & inhibits AgRP/NPY neurones. Informs brain on fat stores. Leptin resistance in obesity.
  4. Leptin and leptin receptor gene mutations – extremely rare monogenic cause of obesity. Johan’s hypothalamic lecture – some key points | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Adapted from M.W. Schwartz 49 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
  5. Dorsal vagal complex (DVC) § nucleus of the solitary tract (NTS), § area postrema (AP) § dorsal motor nucleus of the vagus nerve (DMV) Integrate homeostatic signals about nutritional and energy reserve status. Involved in appetite suppression, malaise, response to infections, gut-brain signals, gastric distension, swallowing etc. Important target for the anorexigenic peptide, GLP-1 (see later) Autonomic control of energy balance: Brainstem | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON DOI:10.1111/nyas.13263 50

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2025-05-05 25 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY 2.Parabrachial nucleus (an anorexic hub) • Relays sensory information to forebrain. • CGRP neurons relay aversive signals (e.g., food poisoning, pain, itch etc) to the amygdala (CeA), the bed nucleus of the stria terminalis (BNST) and other brain regions. • Chronic activation of CGRP neurons can lead to severe anorexia and starvation. • When activated, CGRP neurones block incoming orexigenic information from AgRP neurones in Arc. • Other PBN neurons transmit taste, temperature, respiratory, satiety, thirst, salt- appetite, or glucose counter-regulatory signals. Autonomic control of energy balance: Brainstem | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON CGRP = calcitonin gene- related peptide Anorexigenic https://doi.org/10.1016/j.tins.2018.03.007 51 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY 3. Others The Raphe Pallidus (RPA) receives thermoregulatory information from the hypothalamus and projects to the intermediolateral nucleus (IML) of the spinal cord, from which originate the preganglionic neurons of the sympathetic nervous system (SNS) outflow to BAT. Autonomic control of energy balance: Brainstem | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON POA (Preoptic area), DMH (Dorsomedial hypothalamus) DOI:10.1111/nyas.13263 52

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2025-05-05 26 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Role of the reward system | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Motivation for food, including palatable foods. Pleasure from food and food choice Important when hungry (to help restore energy balance) but also to ensure we eat in excess of metabolic requirement (to help prepare for a future famine). Golocalprov.com 53 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Sustaining energy – eat when available, ­ energy store for future need • Nutrition – variety • Food selection/preference – sweet, salty, umami >> sour, bitter (edible >> poisonous) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Food reward – eating for survival (adaptation) 54

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2025-05-05 27 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Food reward – eating against survival (maladaptation) Vitagazette.com News.bbc.co.cuk 55 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY u They promote eating in the absence of hunger or energy need (= hedonic, non-homeostatic feeding) u Certain foods make us want to eat more (=reinforcement) “Appetite comes with eating; the more one has, the more one would have”. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Food reward – eating for survival 56

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2025-05-05 28 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY “Hunger is the best spice” Swedish Reward value also reflects: Palatability, taste, orosensory experience, reward expectation/prediction, genetics “A good meal ought to begin with hunger”. French | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Hunger increases the reward value of foods 57 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Goldstone et al., 2009, EJN à Brains pathways involved in (visual) food reward processing are regulated by metabolic signals FED FASTED vs ACC amygdala insula ventral striatum lateral OFC medial OFC Brain reward areas:

  • Activated by pictures of rewarding foods.
  • Linked to food reward!
  • Regulated by nutritional state. Δ | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Brain areas linked to reward are more activated by photos of palatable foods when hungry than when fed 58

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2025-05-05 29 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY OFC & Amygdala à reward value of food Insula à taste & hedonic evaluation NAcc, VTA & dorsal striatum à Motivational and incentive properties of rewards Lateral hypothalamus à regulates rewarding response to palatable food and drives reward-seeking behaviours Adapted from Kenny PJ, 2010 Neuron 69: 664 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Brain Areas Activated in Response to Palatable Food or Food Associated Cues 59 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Wanting/motivation Liking/hedonics DOPAMINE (VTA à NAcc) OPIOIDS ENDOCANNABINOIDS Muscle BAT MBH – mediobasal hypothalamus DVC – dorsovagal complex PFC – Prefrontal cortex DVC – Anterior Cinglate Gyrus Dopamine and “friends” DOI:10.1111/nyas.13263 60

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2025-05-05 30 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ventral Tegmental Area (VTA) Nucleus Accumbens (NAc) dopamine The midbrain dopamine neurones signalling reward VTA é Cell firing NAc é dopamine release Natural and artificial rewards + sex food gambling drugs alcohol | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Theguardian.com Rodin Picasso Cezanne Jean Kieffer Adriaen Brouwer 61 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY dopamine Ventral Tegmental Area (VTA) Nucleus Accumbens (NAcc) What does accumbal dopamine actually signal? u Pleasure of eating (Small et al, Neuroimage 2003) u Novel (unexpected) rewards (Norgren et al, Physiol Behan, 2006) u Reward anticipation (cue- induced eg smell) (Epstein et al, Psychol Rev, 2009) u Motivational/incentive value (Volkow et al, Synapse, 2002) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Increases “wanting” and approach behaviour for food Picturequotes.com Golocalprov.com 62

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2025-05-05 31 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Food Reward Generation Food Intake “Gluttony” Hypothesis Reward “Reward deficiency” Hypothesis Reward http://commons.wikimedia.org /wikiCategory:Animations_from _Anatomography Evidence favours a reward deficiency hypothesis | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Obesity is associated with an altered reward function Rubens 63 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY ↓ Striatal dopamine D2 receptor availability in obese subjects. (Similar to drug-addicted subjects). lean morbidly obese … supports the reward deficiency hypothesis in obesity Volkow et al. 2008, Phil. Trans. R. Soc. B 363:3191 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Obesity is associated with an altered reward function 64

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2025-05-05 32 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Potential “reward” contributors to obesity:

  1. Genetic and other pre-existing differences in reward function
  2. Intake of palatable food as an escalating, addictive process
  3. Changes in reward function that are secondary effects of the obese state. Could some obese patients be food addicted? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Obesity is associated with an altered reward function Rubens 65 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Probably not a chemical-like addiction. In man, there is no solid evidence that any food, ingredient, combination of ingredients or additive (exception = caffeine) causes us to become addicted to it! More likely a behavioural addiction. Certain obese individuals appear to express addiction-like behaviour to food eg binge eating disorder http://www.neurofast.eu/consensus/ | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Could food be addictive? 66

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2025-05-05 33 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY See Ziauddeen H et al., 2012, Nat Rev Neurosci Tolerance Dependence Withdrawal Failed abstinence Preoccupation Continued use despite known consequences Many addiction criteria are difficult to apply to food and require severity or impairment thresholds | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 67 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY

Food addiction score Food receipt: Activation in medial OFC Gearhardt AN et al., 2011, Arch Gen Psychiatry Questionnaire à Food addiction score fMRI brain imaging à Areas activated by anticipation & receipt of palatable food. Correlations and comparisons “Food addicted” subjects - differing brain activity response – both for food anticipation and receipt. fMRI response in OFC | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON People that score high on the Yale Food Addiction Scale have a different brain response to food 68

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2025-05-05 34 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The cortical executive system and the decision to eat. PFC circuits (incl. ACC) are close to and influenced by the adjacent olfactory, gustatory, and somatosensory cortices, which compose the insula. Receive sensory information from the oral cavity and digestive tract. Play a decisive role in the eating; the ultimate decision of eating is conscious and voluntary. This can over-ride homeostatic drives, for example. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Pre-frontal cortex Anterior cingulate cortex Insula DOI:10.1111/nyas.13263 69 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Homeostatic metabolic/hormone signals important What kinds of information are signalled to the brain? DOPAMINE (VTA à NAcc) OPIOIDS ENDOCANNABINOIDS DOI:10.1111/nyas.13263 70

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2025-05-05 35 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Δ Feeding behaviour Δ Energy expenditure Δ Adaptive thermogenesis Energy deficit/excess Energy Homeostasis: filling in the gaps | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Executive control systems Reward systems Hypothalamus Brainstem Hunger/satiation /satiety Longterm Short term GUT Pancreas Leptin Other adipokines? Hormones Gastric distension Insulin Others? Fat 71 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Δ Feeding behaviour Δ Energy expenditure Δ Adaptive thermogenesis Energy deficit/excess Energy Homeostasis: filling in the gaps | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Executive control systems Reward systems Hypothalamus Brainstem Hunger/satiation /satiety Longterm Short term GUT Pancreas Leptin Other adipokines? Hormones Gastric distension Insulin Others? Fat Leptin resistance in obesity 72

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2025-05-05 36 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Anti-starvation signal Weight (fat) loss ¯ LEPTIN ­ food intake ¯ energy expenditure ¯ food intake ­ energy expenditure BRAIN BRAIN Ineffective signal due to leptin resistance LEPTIN RESISTANCE Weight (fat) gain ­ ­ LEPTIN Leptin resistance in obesity – the brain no longer “hears” the signal 73 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Eating – for energy requirements & to have reserves | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 74

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2025-05-05 37 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The Brain’s Energy Balance Systems: survival … when food is scarce Reduce metabolism Food searching & consumption | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 75 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Daily energy intake: 2000 kcal Energy stored in fat: 140.000 kcal Impact of a meal on reducing appetite (important) Impact of energy stores (and hence, leptin) on reducing appetite – cannot be the meal- to-meal determining factor on how much we eat. Who drives eating – your fat or your gut? Signals & mechanisms ? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON GUT DOI: 10.1016/j.physbeh.2016.03.038 76

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2025-05-05 38 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The meal cycle: hunger, satiety and satiation | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON I’m full (= satiated) I’m not hungry (=satiety) 77 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Hunger, Satiety & Satiation Meal Stimulatory signals Inhibitory signals Satiation = meal termination Satiety = absence of appetite/hunger until the next meal Eating time Intensity I’m getting hungry I’m full I need to eat | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON NOTE: People commonly confuse satiety & satiation Image: https://www.madlab.ca/are-your- hunger-and- fullness-cues-out-of- whack.html 78

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2025-05-05 39 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY VAGUS Ghrelin PYY Leptin Others? Insulin Others? CCK CNS peptides Marx J, Science. 2003 299:846-9. Murphy K, Bloom SR. Nature 444, 854-859 Anorexigenic (i.e. eat less) A. Increase satiety, B. Increase satiation, C. Cause nausea or aversion, D. For some hormones, their anorexigenic mechanism is unclear (ie. A,B and/or C) Orexigenic (i.e. eat more) E. Increase hunger | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Anorexigenic and orexigenic hormones 79 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GUT Behavioral Responses Autonomic Responses Endocrine Responses ENERGY BALANCE PANCREAS ADIPOSE TISSUE LIVER NUTRIENTS LEPTIN ADIPOKINES PP AMYLIN GLUCAGON INSULIN GHRELIN CCK PYY (3-36) GLP-1 OXM NPY AgRP POMC CART | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 80

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2025-05-05 40 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Important gut hormones for energy balance Ghrelin Gastrin GLP-1 GLP-2 Oxyntomodulin PYY(3-36) FGF19 CCK Secretin GIP Motilin | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON GLP-1 and GLP-2 (Glucagon-like peptides), CCK (cholecystokinin), GIP (Gastric inhibitory peptide), Peptide YY 3-36 (PYY3-36), Fibroblast growth factor 19 (FGF19) 81 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Distribution of enteroendocrine cells in gut Ghrelin CCK GLP-1 PYY(3-36) stomach Small intestine bowel Steinert et al., Physiol Rev 2017; 97:411 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 82

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2025-05-05 41 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Cell type Highest density Peptide released G-cells Stomach Gastrin X-cells Stomach Ghrelin ECL- cells Stomach Histamine ??? Stomach & duodenum Gastrin-releasing peptide (GRP) S-cells Duodenum and jegunum Secretin I-cells Duodenum and jegunum Cholecystokinin (CCK) K-cells Duodenum and jegunum Glucose-dependent insulinotropic peptide (GIP). N-cells Ileum Neurotensin L-cells Ileum and Colon Glucagon-like peptide (GLP-1) L-cells Ileum and Colon PYY3-36 D-cells Entire GI tract Somatostatin EC-cells Entire GI tract Serotonin | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 83 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Gut peptides influencing energy balance

  1. PYY (3-36): Ø Anorexigenic. Produced esp. by the ileum, colon and rectum (L cells) in response to feeding/meals. Ø Signals satiety (long inhibition of eating). Ø It is an agonist at the Y2 receptor (ie NPY receptor subtype 2), a presynaptic NPY receptor. (Note: other NPY receptors are post-synaptic). C.f. NPY acting at Y1 post-synaptic receptors that is orexigenic) Ø Target systems: Arc very important for anorexigenic effect. Y2 receptors also located in DVC and amygdala. Ø Obesity does not appear to be associated with reduced PYY3-36 levels although there are promising effects to reduce meal size. Y2 (autoreceptor) Y1 NPY Food intake PYY(3-36) -ve | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 84

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2025-05-05 42 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Batterham et al., Nature 450, 106-109 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON In healthy subjects, PYY(3-36) reduces caloric intake in a buffet meal 85 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Gut peptides influencing energy balance 2. GLP-1 (and oxyntomodulin) Ø Mostly produced in the ileum, in the L cells (that also produce PYY3-36) Ø Proglucagon (precursor for GLP-1, glucagon, glucagon-like peptide-2 (GLP-2) and oxyntomodulin). Ø Circulating levels increase after meals. Ø Exendin 4: GLP-1 receptor agonist (first isolated from saliva of Gila monster lizard). Ø GLP-1 receptors in CNS: especially brainstem (DVC) and hypothalamus (Arc) but also reward system. Acts as a satiety signal. Ø Oxyntomodulin also binds to the GLP-1R Ø GLP-1 and oxytomodulin à↓food intake and ↓food reward. ↓gastric motility. Ø Long-acting GLP-1 agonists now used clinically (e.g., Liraglutide, Semaglutide) Ø Improved glucose homeostasis (via its incretin effects – see glucose lecture from me). Ø Weight loss Gila monster lizard | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 86

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2025-05-05 43 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ozempic (Semaglutide) – anti-obesity drug | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Long acting GLP-1 analogue 87 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Gut peptides influencing energy balance 3. Cholecystokinin (CCK) Ø Produced by I cells in the GI tract (eg duodenum and jejunum) Ø Release increased especially by fat or protein in duodenum Ø Causes meal termination (satiation signal) Ø Also suppresses gastric emptying Ø Two CCK receptors exist (CCK1 and CCK2) and can be found on vagal afferents as well as in relevant brain areas, especially brainstem (NTS, AP, Dra, the dorsal raphe) but also in reward areas. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 88

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2025-05-05 44 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Insulin and amylin. release from beta cells regulated by gut hormones (especially GLP-1 and GIP). • Glucagon. Increases FGF21 release from the liver. • Pancreatic polypeptide (PP) Glucagon Insulin Amylin FGF21 PP | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Pancreatic hormones FGF21

a hormone secreted by the liver

regulates sugar intake and preferences for sweet foods via signaling through FGF21 receptors in the PVN (hypothalamus) 89 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Pancreatic hormones and energy balance

  1. Insulin ØReleased in association with meals. ØInsulin receptors - hypothalamus (NPY, POMC) and brain stem (nucleus tractus solitarius). ØDirect brain action: Reduces food intake (and increases energy expenditure). ØMay act as a satiety signal. Also provides a marker of fat mass (obese individuals have high levels). | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 90

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2025-05-05 45 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Pancreatic hormones and energy balance 2. Amylin – a satiation signal? Ø Produced by pancreatic beta cells Ø Eating triggers release in proportion to caloric load Ø When administered with leptin, a synergistic effect for weight loss was observed. Ø Role: slows appearance of nutrients in blood after meals by (i) ↓food intake (decreased meal size), (ii) slowing gastric emptying, (iii) inhibiting digestive secretions [gastric acid, pancreatic enzymes, and bile ejection]. Ø Centrally acting eg area postrema of the brain stem. Maintenance of body weight loss induced by sustained infusion of amylin + leptin combination requires the presence of both amylin and leptin in diet-induced obese rats. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON doi- org.ezproxy.ub.gu.se/ 10.1038/oby.2009.187 91 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Pancreatic hormones and energy balance 3. Pancreatic polypeptide ØReleased after a meal (and in proportion to caloric load) and reduces food intake acutely. ØSatiation signal? ØChronic administration reduces body weight in genetically obese mice (ob/ob). ØBinds to neuropeptide Y4 and Y5 receptors. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 92

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2025-05-05 46 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ghrelin Food searching & intake ¯ Fat utilization (RQ) ­ Body weight 200 0600 0800 1000 1200 1400 1600 1800 2000 2200 2400 0200 0400 300 400 700 800 Ghrelin (pg/ml) 500 600 Time of day breakfast lunch dinner Empty stomach | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Gut peptides influencing energy balance 4. Ghrelin (hunger signal) Cummings DE et al., 2001; Diabetes 50:1714-9 Hunger GHS-R1A (receptor) GHS-R1A = growth hormone secretagogue receptor 1A Tschöp et, al, 2000, Nature Oxyntic glands 93 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Cummings et al, Am J Physiol Endocrinol Metab Ghrelin: the hormone that decides when you eat? Hunger Score (mm) Ghrelin % baseline Time (% inter-meal interval) Meal 1 Meal 2 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 94

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2025-05-05 47 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ghrelin targets both homeostatic and reward systems to increase food intake and motivation Ghrelin ­ METABOLIC FEEDING ­Food intake ­REWARD BEHAVIOUR ­Food reward ­Food motivation ­Food intake ­Food anticipation Δ Food preference | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Main targets: Hypothalamus (especially Arc). Many brainstem areas Reward system 95 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Lever pressing for sucrose How much work (number of lever presses) is a rat is willing to expend to obtain a sugar reward à an objective measure of reward value Ghrelin à Increased motivation to work for a food reward FR1 à FR3 à FR5 à PR Fixed Ratio Progressive Ratio à 5 min 120 min 30 min Number rewards (sucrose pellets) ** ** ** 0 2 4 6 8 10 saline Ghrelin 0.3 mg/kg Ghrelin FOOD REWARD & MOTIVATION WORK TO
RECEIVE SUGAR FULL/SATIATED RAT | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 96

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2025-05-05 48 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ghrelin: Ø Circulating stomach-derived hormone Ø Produced by the X/A-like cells in the oxyntic glands Ø The enzyme ghrelin-O-acetyltransferase (GOAT), present in these cells, is responsible for acylating ghrelin on serene 3 (makes it active). Ø Increases food intake and food seeking. Ø Ghrelin receptor (GHS-R1A) located in brain areas controlling energy balance (eg hypothalamus, brain stem), reward (eg tegmental areas such as the VTA) also amygdala, hippocampus Ø Physiological role: meal initiation, hunger, reward-seeking (eg for food). Ø Obesity is not associated with hyperghrelinaemia. Ø May be relevant for eating disorders, including those that lead to obesity. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 97 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY AgRP neurones (a target for ghrelin) signal the unpleasantness of hunger. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Method: Optogenetic activation if AgRP neurones when mice are in the left (Blue) chamber. Result. With each of 7 (15 min) sessions they increasingly avoid the chamber in which their AgRP neurones were activated. Conclusion: Mice dislike having their AgRP neurones activated. Likely they are experiencing the unpleasantness of hunger. doi: 10.1038/nature14416 98

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2025-05-05 49 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY hunger satiation satiety Meal time plasma level Ghrelin CCK/Amylin PYY3-36/GLP-1/ oxyntomodulin/insulin Appetite-regulating hormones signal hunger, satiation and satiety 99 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Hedonic feeding behavior Hunger/satiety satiation Meal time plasma level Ghrelin CCK/Amylin PYY/GLP-1/oxyntomodulin/ insulin | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 100

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2025-05-05 50 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Nature Reviews Gastroenterology & Hepatology 1010, 729–740(2013) Endocrine intestinal cells sense nutrients and signal directly to the nervous system Nutrient sensing Gut hormones Brain DOI:10.1038/nn.3211 101 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Several neural circuits respond directly to hormones from intestine, fat, and pancreas | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON •DOI:10.1038/nn.3211 102

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2025-05-05 51 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY So, what causes obesity and what can we do about it? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 103 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Arguing for a genetics component: § People in same environment don’t necessarily have same body weight § The remarkable increase in obesity trends over last few decades cannot be only due to genetics. § Some ethnic groups are more likely to develop obesity) § There have always been some people predisposed to weight gain § Data from twin and adoption studies § Heritability of body weight is 70% (almost as much as that of height 85%) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON How much obesity is genetics and how much is environmental? EndocrineWebPro 104

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2025-05-05 52 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Dizygotic Twins Monozygotic Twins Wardle J et al Am Clin Nutr 2008 Heritability of childhood BMI in UK – 75% Heritability estimates #0.6-0.8 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Genetics of obesity: twin studies 105 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Genetic factors contribute 40-70% to excess body fat. Pima Indians – nomads - scarce conditions but develop obesity when food is available. “Thrifty genotype” hypothesis. Certain genes in humans have evolved to maximize metabolic efficiency and fat storage. In times of plenty, these genes predispose their carriers to obesity and diabetes. Environment gives genetics (Darwin) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Genetics of obesity- interaction with environment Ravussin E et al., Diabetes Care 1994 106

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2025-05-05 53 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY § Few obesity genes known yet (less than 5% of genetically determined obesity). § Monogenic causes (eg gene deletions) rare § POMC/MC4-R deletions - MC4-R; heterozygotes have “middle” phenotype. § Leptin/leptin receptor dysfunction §

300 SNPs linked to obesity traits, emerging from GWAS. Most still of unclear biological significance (eg FTO). The association of the FTO region to obesity explains ~1% of BMI heritability, such that adults homozygous for the risk allele, have a 2–3 kg higher weight compared to non-risk allele homozygous (Frayling TM et al., 2007) FTO = FaT mass and Obesity- associated protein | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Genetics of obesity: known genes that contribute 107 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Manhatten plot • Subtle changes in individual genes impact on body weight. • The more risk alleles you have the more likely you will have a high BMI • Many risk alleles are hypothalamic. 108

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2025-05-05 54 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Source: Giles Yeo Note, semaglutide is a recently approved drug for obesity that is caused by gene defects upstream of MC4R Disruption of melanocortin signalling causes severe obesity 109 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY ØEpigenetics - the study of heritable changes which affect gene function without modifying the DNA sequence. ØEpigenetic markers are tissue specific and include DNA methylation and histone modifications which mediate biological processes such as imprinting. (Note FTO codes for a DNA methylase that turns off genes) ØHypothesis: early environmental influences induce epigenetic variation, thereby permanently affecting metabolism and chronic disease risk. ØEg Epigenetic factors may explain why under or over-nutrition in utero (environment) à ­ risk of metabolic disease in later life.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Epigenetics factors and Obesity 110

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2025-05-05 55 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • The human gut has a diverse microbial ecosystem (>2000 different
species, high inter-individual variability). • Hypothesis: Gut microbiota contribute to the development of obesity and the metabolic syndrome. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Gut microbiota and obesity Evidence: Transplantation of gut microbiota from obese mice to non-obese, germ-free mice resulted in transfer of metabolic syndrome-associated features from the donor to the recipient. 111 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • The human gut has a diverse microbial ecosystem (>2000 different
species, high inter-individual variability). • Hypothesis: Gut microbiota contribute to the development of obesity and the metabolic syndrome. • Evidence: Transplantation of gut microbiota from obese mice to non-obese, germ-free mice resulted in transfer of metabolic syndrome-associated features from the donor to the recipient. • Mechanism currently being researched § provision of additional energy by the conversion of dietary fiber to short-chain fatty acids? § effects on gut-hormone production? § ­ intestinal permeability à systemic levels of lipopolysaccharides (LPS à low- grade inflammation (as seen in obesity/metabolic syndrome)? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Gut microbiota and obesity 112

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2025-05-05 56 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • We have evolved to over-eat available foods to prepare for a future famine. • People with genetic obesity are fighting their biology. Prone to make unhealthy decisions around food, for example. • Obesogenic caloric foods are energy-dense and it is easy to overconsume them, even when full. • All diets that reduce caloric intake or decrease energy expenditure work – if we keep to them. Why do they fail? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON But what about dietary control? Dessert when full The happyfoodie.co.uk 113 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Decreased leptin is important when dieting – turns on the starvation response: over-eating, ↑ reward value of food, save energy for brain, switch off costly energy functions (e.g. reproduction, immune system). • The threshold to respond to a dieting-induced fall in circulating leptin may be higher in obese individuals, making it hard for them to reduce food intake. • When hungry (or dieting) food cues are increasingly attractive and it becomes hard to resist food. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Why don’t diets work? 114

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2025-05-05 57 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY _ _ Intense hunger Food craving (Neuro)biological adaptations Dietary failure Weight gain Caloric Restriction Dieting | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON https://www.upmcmyhealthmatters.com/the-5-ds-of-dieting/ 115 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY ! "!! #!! $!! %!! &!!! '()+', -./ )0+1 Caloric intake per day Caloric intake sugar fat chow normal diet normal diet extra fat normal diet extra fat and sugar hedonic feeding | INST NEUROSCIENCE & Study in rodents given choice diets. Adan RA & LaFleur SE The more to choose, the more calories are eaten 116

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2025-05-05 58 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY ! "# #! $# %!! !

%! %# "! "# &! &# '(FH,-./01 23-/H4(5S'H5.(7H,51 8S34 9:9; ! "! #!! #"! A!! #%&''( "%&''(F %H,H-%.%/0%12/&%34/5ST 12/& 898W * * * * | INST NEUROSCIENCE & Animals on a high fat-high sugar (HFHS) diet gain weight 117 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY ! "! #!! #"! A!! %C' C()* +,%-./M.NO.P4NR6 * * | INST NEUROSCIENCE & Animals on a high fat-high sugar (HFHS) diet become leptin resistant & have a “hungry” neuropeptide profile Effect of leptin injection on food intake HFHS-choice diet: insensitive to leptin – it doesn’t suppress food intake HFHS Control diet HFHS-choice diet: hypothalamic gene changes similar to hunger à eat more! 118

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2025-05-05 59 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY _ _ Intense hunger Food craving (Neuro)biological adaptations Dietary failure Weight gain Caloric Restriction Dieting How can we break the cycle? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON https://www.upmcmyhealthmatters.com/the-5-ds-of-dieting/ 119 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Breaking the viscous cycle of weight gain: bariatric surgery à improved food reward control (Neuro)biological adaptations Dietary failure _ _ _ _ Bariatric surgery (eg gastric bypass) Weight gain Intense hunger Food craving Caloric Restriction Dieting We need to understand how/why bariatric surgery works | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 120

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2025-05-05 60 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Bariatric (weight loss) surgery Gastric banding Vertical banded gastroplasty Gastric bypass Only effective Obesity therapy | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 121 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Swedish Obese Subject study: Weight loss after bariatric surgeries Change in Body Weight (%) control banding Ventral-banded gastroplasty Gastric bypass Sjöstöm L et al NEJM 2004 122

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2025-05-05 61 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Gastric bypass surgery à weight loss and reduced mortality. Life expectancy ­ by 12 years. Swedish Obese Subject study: Mortality 123 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The future: Novel obesity therapies that “bypass” gastric bypass? (Neuro)biological adaptations Dietary failure _ _ _ _ Bariatric surgery (eg gastric bypass) Weight gain Intense hunger Food craving Caloric Restriction Dieting ¯ Ghrelin ­ PYY ­ GLP-1 It is not yet clear that these changes in hormone levels
are important for the weight loss after gastric bypass!!! | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 124

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2025-05-05 62 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Gastric Bypass surgery: Physiology Food enters small gastric pouch à fullness sensed (nervous) Discomfort & vomiting if over-eat. When food enters small intestine à Anorexigenic hormones released eg CCK (duodenum), GLP-1 & PYY(3-36) (ileum) Mechanism Decreased container function /restriction? Probably not – other restrictive procedures are less effective. Malabsorption? Certainly not a primary mechanism. Increased energy expenditure (eg could involve increased bile salts taken up into blood). Increased anorexigenic signals after meals and/or decreased ghrelin before meals? Hormones likely contribute to weight loss success. Improved food choice – brain reward system implicated. Others? Eg microbiota, nutrient sensing by gut. … actually … we don’t really know. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 125 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Anti-obesity drugs: possible mechanisms? Ø Decrease food intake (reduce hunger, reduce reward, increase satiety, delay meal initiation, reduce portion size, improve choice) Ø Decrease gut uptake of nutrients Ø Increase energy expenditure (ie the use of energy by the body). Longterm effects only persist if we can reduce the ”set point” (ie make an individual percieve their energy homeostasis to be set at a level lower that it is). | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 126

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2025-05-05 63 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Energy Balance Fluctuations Over a Day Adan RA, TINS, 2013, 36: 133–140 -ve +ve Preventative and treatment strategies for obesity should target especially food intake. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 127

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