Week 3 Lecture

Homeostatic regulation of energy balance

Bonnie Beezhold, PhD, CHESAssistant Professor, Nutrition

Benedictine University

1

What influences eating behaviors?

Homeostatic eating relates to hunger and satiety, energy balance and weight management

Nonhomeostatic eating is influenced by hedonic properties, and relates to eating in the absence of hunger http://www.thesun.co.uk/

Energy intake regulation terms

Hunger: physiological demand for calories due to low blood nutrient levels

Appetite: psychological demand for food influenced by the senses

Satiation: the feeling of fullness resulting from the presence of food in the gut relayed by nervous and hormonal signals

Satiety: the absence of hunger resulting from circulating nutrients and hormones

GO mechanisms

STOP mechanisms

Brain integration of homeostatic and non-homeostatic signals in energy intake regulation

Cornier, 2011

http://en.wikipedia.org/wiki/Diencephalon

Hypothalamus and brain stem

http://scientopia.org/

Gut-brain axis

Neural and endocrine signals from and to the brain and gut affect energy expenditure via the autonomic nervous system.

Short-term intake regulation

Postprandial (after meal) control of hunger and satiety

Distention of stomach activates gastric stretch receptors and mechanoreceptors that transmit satiety signals

GUT-derived signaling pathways to the brain regulating meal initiation or termination are the primary control

Long-term intake regulation

Endocrine action of adipose tissue to achieve balanced BMR

Leptin and insulin are signals of long term energy stores, modulated according to fluctuations in energy reserves

Obesity trends and lack of treatment success may indicate that this regulation is more potent in protecting against energy deprivation

Image from http://www.vetmed.vt.edu/education/

Factors that affect homeostatic feeding

Neural signals resulting from mechanical distension and chemical stimulation by nutrients present in the gut

Bloodborne signals related to body energy stores resulting from nutrient or hormone levels such as low plasma glucose levels (stimulates hunger)

Hormones and neurotransmitters circulating in the blood such as insulin (depresses hunger) and epinephrine (stimulates hunger)

Orexigens and anorexigens are chemicals released that influence feeding behavior

The next several slides are graphic summaries about the melanocortin system in the arcuate nucleus (ARC), a powerful regulator of appetite and satiety.

Melanocortin system

The NPY/AgRP orexigenic neurons release the peptides NPY and AgRP and the inhibitory neurotransmitter GABA.  They project to the lateral hypothalamus and upon activation, stimulate feeding.  During periods of fasting, NPY concentration in the ARC is increased and causes excessive eating.  These neurons carry out the appetite regulatory effects of leptin and ghrelin, however if the NPY gene is knocked out, mice still respond normally to leptin because leptin has other target sites, the POMC neurons. (Flier & Maratos-Flier, 1998)

http://www.diabesity.eu/cntf.htm

Stimulation of appetite

The POMC anorexigenic neurons receive projections from the NPY neurons and also mediate leptin and ghrelin. POMC neurons produce two different peptides, the β endorphins and the melanocortins. The melanocortin alpha melanocyte stimulating hormone (α-MSH), a powerful inhibitor of appetite, acts on the melanocortin receptors MC3 and MC4. At the end of feeding POMC neurons are activated and release α-MSH to inhibit appetite.  (Cone, (2005)

Suppression of appetite

http://www.nature.com/nrn/journal/v5/n8/fig_tab/nrn1479_F2.html#figure-title

↓ stored fat & leptin

(+) NPY/AgRPneurons

(-) of POMC

Weight gain

↑ stored fat & leptin

(-) NPY/AgRPneurons

(+) of POMC

Weight loss

POMC neurons (ά-MSH system) are inhibited; NPY promotes hunger, inhibits satiety weight gain (endogenous antagonist of MC4 receptor)

Leptin and ghrelin in energy imbalance

Despite the function of leptin to decrease appetite, slowly rising leptin levels occurring in weight gain do not prevent obesity

Ghrelin is reduced in obesity (negatively correlated with BMI) and in sustained energy restriction (dieting)

GLP-1 and PYY are also reduced in obesity

Doucet & Cameron, 2007; Klok, 2006

Hunger and satiety in the reduced-Obese state

M.A. Cornier, G.K. Grunwald, S.L. Johnson and D.H. Bessesen, Effects of short-term overfeeding on hunger, satiety, and energy intake in thin and reduced-obese individuals. Appetite,  43  (2004), pp. 253–259

Mean (± SEM) pre-meal hunger (A) and post-meal satiety (B) during eucaloric and overfeeding diet periods are shown. Overfeeding resulted in significant reductions in mean pre-meal hunger and increases in mean post-meal satiety in thin as compared to reduced-obese individuals.

Adiponectin is the most prevalent hormone in fat cells The main function is to promote fat oxidation and insulin

signaling Reduced levels are observed with obesity

Leptin

Adiponectin

Resistin

Adiponectin

Oxyntomodulin

Released postprandially from the gut in proportion to kcals consumed

It binds to the GLP-1 receptor in ARC and inhibits gastric acid secretion, reduces food intake, and promotes energy expenditure

A. After an injection of oxyntomodulin, volunteers ate on average 128 Kcal or 17.3% less without altering their enjoyment of food. B. The participants’ energy expenditure due to activity was markedly increased by 143 Kcal/day or 26.2% during the period of oxyntomodulin treatment. C. The increase in activity resulted in an increase in total energy expenditure of 9.4%, although REE was unchanged. D. These overweight and obese people started with expected low levels of physical activity, but oxyntomodulin administration increased physical activity back toward normal levels, resulting in more energy being used each day. These findings suggest that oxyntomodulin has a double effect of suppressing appetite and concurrently increasing physical activity toward normal levels.

A double-blind, placebo-controlled study was performed in which 15 healthy overweight and obese volunteers were trained to give themselves oxyntomodulin injections under the skin, just before each meal, three times daily. Food intake and energy expenditure were measured over four days and compared with a similar period during which the same volunteers administered a saline placebo. Food intake was provided in excess and the volunteers ate until they felt full. Activity-related energy expenditure was calculated from combined heart rate and movement monitoring in the participant’s normal environment. REE was calculated using indirect calorimetry.

Wynne et al, 2005, 2006

Bottom line

After weight loss, energy balance-related biologic signals are powerfully enhanced to promote increased energy intake and reduced energy expenditure, setting up for weight regain

Therapies targeting appetite circuits and administering low doses of a combination of gut hormones appear more promising than therapies targeting the central nervous system