FOOD REWARD AND MODULATION BY NUTRITIONAL STATUS, INSULIN AND LEPTIN. Dianne Figlewicz Lattemann, Ph.D.

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1 FOOD REWARD AND MODULATION BY NUTRITIONAL STATUS, INSULIN AND LEPTIN Dianne Figlewicz Lattemann, Ph.D. ECOR SYMPOSIUM FEBRUARY 23, 2006 PASSION LIVES HERE, TOO

2 Model for regulation of body adiposity

3 Hypothalamic Areas Regulating Energy Balance Arcuate Nucleus Abundant leptin and insulin receptor expression Neuropeptides involved in energy homeostasis and regulated by adiposity signals.

4 Schwartz MW and Morton GJ. Nature 418: , 2002

5 Downstream of the Arcuate Nucleus:

6 VTA/SNC Striatum/ NAcc Pallidum Motor Programs Amygdala/ Hippocampus/ PF Cortex PPTN LH PVN ARC PBN NTS Oral sensory and Motor Programs

7 VTA/SNC Striatum/ NAcc Pallidum Motor Programs Amygdala/ Hippocampus/ PF Cortex PPTN LH PVN ARC PBN NTS Oral sensory and Motor Programs

8 Insulin and leptin act directly in the CNS to decrease performance in reward behavior paradigms: 1. Brain self-stimulation (Fulton 2000; Carr 2000) 2. Food-restriction stress induced relapse to drug-taking (Shalev 2001)

9 Insulin and leptin act directly in the CNS to decrease performance in reward behavior paradigms: 1. Brain self-stimulation (Fulton 2000; Carr 2000) 2. Food-restriction stress induced relapse to drug-taking (Shalev 2001) 3. Food reward/motivation (Lattemann lab)

10 Conditioned place preference (CPP) evaluates learned association of a place with a rewarding experience.

11 Sucrose or chow pellets condition a place preference in food-restricted but not ad lib fed rats Effect of Food Restriction on CPP to Low-Calorie Sucrose and Chow Pellets Difference Score Sucrose Chow 10 Pellets/ training session Ad lib Restricted

12 Low leptin levels contribute to CPP in food-restricted rats. Figlewicz et al. 2001

13 IVT insulin and leptin block CPP to high fat diet in ad lib fed rats. Figlewicz et al, CPP Score ad lib Fed CSF **p=0.05, ad lib/ins vs. FR/Ins *p=.003, ad lib/lep vs FR/Lep

14 IVT insulin and leptin block CPP to high fat diet in ad lib fed rats. 200 Figlewicz et al, Behav. Neurosci CPP Score ad lib Fed CSF Leptin Insulin **p=0.05, ad lib/ins vs. FR/Ins *p=.003, ad lib/lep vs FR/Lep

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17 Self-administration evaluates the motivation (willingness to work for) a reward such as drugs, intra-cranial electrical pulse, or food.

18 100 Training for sucrose Rewards (6 h) (n=26) Day Grimm and Shaham, NIDA Sucrose self-administration: evaluating the motivating qualities of food. 1. Constant schedule bar pressing see above. 2. Progressive ratios rats press the bar an increasing number of times to obtain a sucrose reward.

19 Motivated work for sucrose solutions is modified by nutritional status.

20 IVT insulin and leptin decrease 5% sucrose selfadministration in non-deprived rats. ACTIVE LEVER PRESSES

21 Motivated work for food reward (baseline performance) may be increased by a more palatable food reward (chocolate Ensure).

22 Motivated work for food reward (baseline performance) may be enhanced by a higher-fat chronic diet.

23 The effectiveness of IVT insulin or leptin can be modified by changing the rewarding food or changing the chronic diet of the rats. 150 # PRESSES ON ACTIVE LEVER AS % OF CSF DAY (WITHIN-SUBJECTS) 100 *p<0.05 vs. CSF % SUC n=30 5% SUC/SSM n=13 10% SUC n=23 INSULIN LEPTIN

24 Where in the CNS are insulin and leptin acting to modulate food reward? 1. Via Arcuate/PVN circuitry 2. LH 3. VTA/NAc 4. Amygdala

25 Cellular and behavioral evidence supports the possibility that the VTA DA neurons can be direct targets for insulin or leptin: 1. Presence of insulin and leptin receptors 2. Activation of the PI3 kinase/pkb pathway 3. Regulation of a key synaptic protein, the DA re-uptake transporter 4. Suppression of sucrose treat feeding and chow intake.

26 The VTA/Substantia Nigra Circuitry Paxinos 1995

27 SN TH and GAD neurons

28 VTA TH and GAD neurons

29 Insulin receptors and leptin receptors are expressed on VTA dopamine neurons. Figlewicz et al., 2003 Insulin receptor/th co-expression Leptin receptor/th coexpression

30 Insulin receptors may be expressed in GABA neurons within the VTA. (Naleid, unpublished)

31 Leptin Insulin JAK STAT IRS PI3K IRS MAPK PIP3

32 Insulin and leptin increase PIP3- immunoreactivity within the VTA.

33 From Dr. Ralph DiLeone: Top panel: In situ, low power showing Lepr (ObR) mrna in the VTA of rat Middle panel: In situ, higher power, showing that Lepr is in TH neurons only (but clearly not all TH neurons) Bottom panel: Western showing pstat3 response in VTA punches 2h after IP leptin (2mg/kg) treatment of mice

34 DA Terminal and Synapse: The DAT terminates DA signalling by clearing DA from the synapse. DA DA DA DA DAT DA DA DA DA NEURON D 2 RECEPTORS DA DA DA DA DA DA DA DA

35 In vitro Voltammetry of DA Uptake in Striatum 1.5 µm Dopamine 1.5 µm Dopamine + Mazindol or Cocaine 3 minutes

36 INSULIN + DAT - DA Clearance DA Signalling FASTING

37 IVT insulin increases the expression of the DA reuptake transporter (DAT) in the VTA. Figlewicz et al. 1994

38 Acute food deprivation results in decreased expression of the DAT in the VTA. Free-feeding Fasted

39 Acute food deprivation results in decreased activity of the DAT in the striatum, which is restored by insulin in vitro. Patterson et al 1998

40 Insulin stimulates DA uptake by recruiting DATs to the cell membrane. (A. Galli and colleagues) Fig. 1 A CTR AMPH30 Ins+AMPH CTR AMPH40 AMPH+Ins B Biotinylated hdat Total CTR Ins 40 Biotinylated hdat C D Total Biotin. hdat Density (% of control) # Biotin. hdat Density (% of control) # 0 CTR AMPH30' Ins+AMPH 0 CTR AMPH40' AMPH+Ins

41 Mu opioid agonists stimulate feeding in the VTA by inhibiting GABA neurons. Paxinos 1995 Mu opioid - GABA - DA

42 Intra-VTA DAMGO injection stimulates food intake which is blocked by D1 DA antagonist in the nucleus accumbens. MacDonald, Levine and Billington 2003

43 Unilateral intra-vta insulin or leptin reverse the effect of a mu agonist to stimulate sucrose intake.

44 Bilateral VTA injection of leptin decreases 24 hr chow intake. (Ralph DiLeone and colleagues)

45 Concluding Remarks 1. Insulin, leptin, and other metabolic signals (ghrelin) can modulate food reward: a. Feeding caused by direct stimulation of reward circuitry; b. Learned association between place and rewarding food; c. Motivated work for rewarding food. 2. IMPLICATION: Our findings suggest that all of these aspects of food reward (learning/motivation/ wanting ) may be amenable to pharmacological or pharmacotherapeutic intervention.

46 The REAL Dream Team: ACKNOWLEDGMENTS Anatomy: Sepideh Aliakbari Salwa Al-Noori, Ph.D. Jen Bennett Wendi Daumen Charles Davis Pam Gronbeck Mike Higgins Amy MacDonald Naleid, Ph.D. Dr. Denis Baskin Dr. Kevin Niswender Dr. Patti Szot Colleagues-at-large: Dr. Stephen Benoit Dr. Karl Kaiyala Behavior (NIDA): Dr. Jeff Grimm Dr. Yavin Shaham Scott Ng-Evans, Ph.D. Nicole Sanders, Ph.D. Al Sipols, Ph.D. M.D. Garrett Stuber Connie Holmes West Aryana Zavosh Financial Backing: NIH/NIDDK Dept of Veterans Affairs Merit Review Program and Research Career Scientist Program The Metabolism Group PASSION LIVES HERE, TOO