Dr Alex Johnstone

Protein, satiety and satiation

BNF London, 18th June 2009

‘obese people and those desiring to lose weight should perform hard work before food. Meals should be taken after exertion and while still panting from fatigue. They should, morever, only eat once per day and take no baths and sleep on a hard bed and walk naked as long as possible’

Hippocrates, 5th century B.C.

Obesity – not a new problem !

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Weight loss is easy - energy intake < expenditure

• Hunger is one of the main reasons why people fail to comply to a weight loss diet

• How can we develop dietary strategies that fulfill hunger and still achieve weight loss ?

• Macronutrient composition of the diet is important to contribute to satiety during weight loss

Protein and appetite control for weight loss

Protein – satiation or satiety ?

• Satiety - between meal interval• Post-ingestive and post-absorptive

consequences (gut – brain axis)

• Satiation - within meal• Feeding rate & meal size

Protein – satiation or satiety ?Inter- meal interval is increased in mice fed a high whey, as opposed to soy and gluten, protein diets. Yu et al (2009) Appetite, 52,372–379.

Inter-meal intervalMeal numberMeal sizeMeal durationRate of ingestionWithin meal pausesEnergy intake

• Whey protein most potent satiety effect (inter-meal)

• Similar effects in preloading studies in humans (~50g)

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Weight Loss (kg) DifferenceStudy n Low-fat Low-carb (kg)Samaha(2003) 132 -1.9 -5.8 3.9

Brehm(2003) 42 -3.9 -8.5 4.6

Foster(2003) 63 -5.3 -9.6 4.3

Yancy(2004) 120 -6.5 -12.0 5.5

• Weight loss difference, in part due to glycogen and water loss• At 12-months the difference is greatly reduced

Weight loss is greater on high-protein, low carbohydrate diets

Weight loss at 6-months in RCTs of low-fat vs low-carbohydrate dietsRecently, there has been increased interest in the use of low-carbohydrate diets

as potential therapy for obesity. The results of five RCTs in adults [1-5] found that subjects randomized to a low-carbohydrate, high protein/high fat diet (approximately 25-40% carbohydrate) achieved greater short-term (6 months) [1-4], but not long-term (12 months) [3, 5], weight loss than those randomized to a low-fat diet (approximately 25-30% fat, 55-60% carbohydrate). A consistent difference in weight loss at 6 months was observed between groups across studies; subjects randomized to the low-carbohydrate diet lost 4-5 kg more weight than those randomized to the low-fat diet. The data from these studies also found greater improvements in serum triglyceride and HDL-cholesterol concentrations, but not in serum LDL-cholesterol concentration, in the low-carbohydrate group than in the low-fat group. In addition, glycemic control was better with low-carbohydrate than a low-fat diet therapy in subjects who had type 2 diabetes [1, 5].

1. Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J,Williams T, Williams M, Gracely EJ, Stern L: A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med 348:2074-2081, 2003.

2. Brehm BJ, Seeley RJ, Daniels SR, D'Alessio DA: A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol.Metab 88:1617-1623, 2003

3. Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS,Szapary PO, Rader DJ, Edman JS, Klein S: A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 348:2082-2090, 2003.

4. Yancy WS, Olsen MK, Guyton JR, et al. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia. Ann Intern M d 2004 140 769 777

Protein effect ?

• Nutritionist question the effect on health ?

• Mechanism of appetite control?

• Role of low carbohydrate (ketosis)- additive effect ?

Diet composition can affect hunger and appetite control, for weight loss: high-protein, low-carb diets

• Popular with dieters - eat less but feel lesshungry - the ‘holy grail’ of dieting ?

• What is the role of the low-carbohydrate componentin high protein diets ?

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High protein weight loss dietsMean Weight Los

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•• Weight loss is significantly more on Weight loss is significantly more on the highthe high--protein, protein, ketogenicketogenic diet diet (p=0.006)(p=0.006)

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•• Hunger is significantly less on the Hunger is significantly less on the highhigh--protein, protein, ketogenicketogenic diet diet (p=0.020)(p=0.020)

•• Ad Ad libitumlibitum intake is significantly less intake is significantly less on the highon the high--protein, protein, ketogenicketogenic diet diet (p=0.020)(p=0.020)

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Maintenance

Ketogenic Non-ketogenic

Johnstone et al. (2008) AJCN 87:44-55.

Results - metabolic health

• Reduction in HOMA (insulin resistance)(p<0.017)

• Reduction in cholesterolon both diets (p=0.022)

Johnstone et al. (2008) AJCN 87:44-55.

HOMA-IR

Total cholesterol (mmol)

Pre WL Post WL

Pre WL Post WL

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Whole body PET scanDynamic radio-nucleotide imaging tool

Chief Scientist Office

Positron emission tomography (PET)

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HypothesisGlucose uptake and metabolism differs within key areas of the brain known to be involved in intake regulation?

Appetite research: PET scan study

HP-LC and HP-MC weight loss diets

Nutritional challenges impact on brain metabolism and motivation to eat, which can be detected by Positron Emission TomographyJohnstone, Broom, Welch & Lobley et al. IJO, 2008

Appetite Research: PET Scan study

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Maintenance

Ketogenic Non-ketogenic

• What about comparison of normal protein (NP) and high-protein (HP) ?

Appetite ResearchProtein induced satiety

• Compared two high protein diets – both significantly reduced ad libitum intake, relative to maintenance

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Ad lib intake and body weight

• Increasing protein intake from 15 to 30% produces sustaineddecrease in ad libitum intake

Hunger and fullness ratings

Weigle et al. (2005) Am J Clin Nutr 82, 41-8.

High-protein diet reduces ad lib intake

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• Peptides or amino acids Does dietary supplementation of amino acids withina normal-protein weight loss diet, change profile of‘motivation to eat’ to that similar on a high-proteinweight loss diets ?

• Bio-markersAre alterations in plasma amino acids or gut-relatedhormones signals for altered appetite response or‘motivation to eat’ ?

Mechanisms of protein induced satiety

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Gut-peripheral interactions for energy balance

Badman et al. (2005) Science 307, 1909-14.

Fig. 1. The brain integrates long-term energy balance. Peripheral signals relating to long-term energy stores are produced by adipose tissue (leptin) and the pancreas (insulin). Feedback relating to recent nutritional state takes the form of absorbed nutrients, neuronal signals, and gut peptides. Neuronal pathways, primarily by way of the vagus nerve, relate information about stomach distention and chemical and hormonal milieu in the upper small bowel to the NTS within the dorsal vagal complex (DVC). Hormones released by the gut have incretin-, hunger-, and satiety-stimulating actions. The incretinhormones GLP-1, GIP, and potentially OXM improve the response of the endocrine pancreas to absorbed nutrients. GLP-1 and OXM also reduce food intake. Ghrelin is released by the stomach and stimulates appetite. Gut hormones stimulating satiety include CCK released from the gut to feedback by way of vagus nerves. OXM and PYY are released from the lower gastrointestinal tract and PP is released from the islets of Langerhans.

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Potential action of gut peptides on the hypothalamus

Badman et al. (2005) Science 307, 1909-14.

Fig. 2. Simplified representation of potential action of gut peptides on the hypothalamus. Access circulating agents into the arcuate nucleus of the hypothalamus is facilitated by a relaxed blood-brain barrier. Primary neurons in the arcuate nucleus contain multiple peptide neuromodulators. Appetite-inhibiting neurons (red) contain pro-opiomelanocortin (POMC) peptides such as melanocyte-stimulating hormone (MSH), which acts on melanocortin receptors (MC3 and MC4) and cocaine- and amphetamine-stimulated transcript peptide (CART), whose receptor is unknown. Appetite-stimulating neurons in the arcuate nucleus (green) contain neuropeptide Y (NPY), which acts on Y receptors (Y1 and Y5), and agouti-related peptide (AgRP), which is an antagonist of MC3/4 receptor activity. Integration of peripheral signals within the brain involves interplay between the hypothalamus and hindbrain structures including the NTS, which receives vagal afferent inputs. Inputs from the cortex, amygdala, and brainstem nuclei are integrated as well, with resultant effects on meal size and frequency, gut handling of ingested food, and energy expenditure. , direct stimulatory; ---|, direct inhibitory; - - ->, indirect pathways.

Plasma PYY after iso-energetic meals

Batterham et al (2006) Cell Metabolism 4, 223-233

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Fixed intake on a HP, NP, NP-AA and NP-MTD

Obese men (n = 20)

Amino acid protocol

So now I am going to show you the design of the study.•Vols on Fixed intake for 4 weeks on each intervention diet with a maintenance period at the start•For simplicity from now on HP-LC = K, HP-MC = NK•Rotation of the crossover between K & NK diets was randomised

Measurements taken:•Weekly blood samples•Anthropometric – BodPod, BP, DXA, Skinfolds•Daily urine spot samples to monitor levels of ketosis•Daily Hunger & Satiety questionnaires using VAS•Glucose Infusions•PET Scans

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• Fixed intake on a HP, NP, NP-AA and NP-MTD (100% RMR)• Obese men, healthy (n = 20)

Protocol

HP NP NP-AA30% Protein 15% Protein 30% Protein30% Fat 30% Fat 30% Fat40% CHO 55% CHO 40% CHO

Weight loss, body composition, metabolic rateHunger (VAS)Plasma amino acid profileMetabolites/hormones/inflammation/CVD risk factorsIsotopic approach to metabolism

So now I am going to show you the design of the study.•Vols on Fixed intake for 4 weeks on each intervention diet with a maintenance period at the start•For simplicity from now on HP-LC = K, HP-MC = NK•Rotation of the crossover between K & NK diets was randomised

Measurements taken:•Weekly blood samples•Anthropometric – BodPod, BP, DXA, Skinfolds•Daily urine spot samples to monitor levels of ketosis•Daily Hunger & Satiety questionnaires using VAS•Glucose Infusions•PET Scans

‘Not at all hungry’ (mm)

‘Extremely hungry’ (mm)

HP‐High protein weight loss

NP‐Normal Protein weight lossHP‐Amino acid weight loss

Hunger data Diet effect (p=0.040)

AA

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Stable isotope protocol:Oral and i.v. Leucine and Phenyalanine

breakfast lunch

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Soya vs meat protein: effect on appetite

• High protein diets are a useful tool for short-term weight loss : 30% of restricted energy

• Do not need reduced carbs for appetite control

• Type of protein ?

• Interaction with energy density ?

Conclusions

MEDIA - Don't be a silly sausage with diets –soya banger can beat the bulge

Scotland on Sunday, 15th JuneIT IS the Mount Everest of the health campaigner –persuading Scottish men to give up their love affair with fried sausage and bacon, fatty mince, and giant plates of steak

‘ECO-ATKINS’ - University of Washington School of Medicine study points to potentially safer low-carbdiets for people with heart problems

Vegetarian Atkins diet lowers heart risks –

studyMonday, June 8

09:58 pm, Reuters

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‘Our obesogenic environment makes it easy to gain weight; weight loss is difficult. Development of preventative dietary strategies to control appetite and improve health will assist in achieving weight control.’

Johnstone, 2008

‘Most people will not stay in treatment for obesity. Of those who stay in treatment, most will not lose weight, of those who do lose weight, most will regain it.’

Stunkard,1958

Final thought