Lep­tin is a hor­mone exclu­sively pro­duced by fat cells that may have wide impli­ca­tions for sugar metab­o­lism (1), hedo­nis­tic behav­ior such as over-feeding (2).

Overeat­ing may be a form of addic­tion, and lep­tin may play a cru­cial role with other neu­ro­hor­mones such as dopamine in medi­at­ing crav­ings for highly-palatable & “reward­ing” food high in sugar, salt, and fat (3; 4).

Lep­tin lev­els ini­tially act to mon­i­tor fat mass, help reduce appetite and ulti­mately con­trol weight. But as lep­tin resis­tance devel­ops, weight man­age­ment can become increas­ingly dif­fi­cult to control.

Con­cen­tra­tion of lep­tin reflects fat stores sig­nal­ing the brain about the body’s energy sta­tus (5).

Lep­tin does so by act­ing on an area in the brain known as the hypo­thal­a­mus to sup­press food intake and increase energy expen­di­ture through action of the sym­pa­thetic ner­vous sys­tem (6; 7; 8).

In the case of eat­ing behav­ior and obe­sity, lep­tin has an indi­rect effect on insulin release through its higher effect on the ner­vous sys­tem (9), but also has direct effects on glu­cose trans­port and insulin activ­ity (10; 11; 12; 13).

Lep­tin is a hor­mone with diverse func­tions and effects on the body:

• Inde­pen­dent of food intake, lep­tin along with the affect of other hor­mones, may alter the metab­o­lism of fatty acids by its action on the hypo­thal­a­mus (14).
• Lep­tin imbal­ance may dam­age liver cells (15; 16), as well as the pan­creas, platelets, blood ves­sels and heart mus­cle (17).
• Lep­tin release may con­tribute to sus­cep­ti­bil­ity to autoim­mune dis­ease due to affect on immune tol­er­ance and respon­sive­ness (18)
• May be impli­cated in chronic kid­ney dis­ease (19; 20)
• Lep­tin may play medi­at­ing role in innate immune responses and aller­gic responses. (21), and also inflam­ma­tion (22).
• May play mod­u­lat­ing role in rheumatic dis­eases (rheuma­toid arthri­tis), includ­ing car­ti­lage, syn­ovium, bone and immune cells (23).
• Higher con­cen­tra­tions of lep­tin may pos­si­bly stim­u­late tumor growth and con­tribute to “meta­bolic bur­den” (24; 25)
• Lep­tin defi­ciency may cause obe­sity, dia­betes, and other endocrine prob­lems (26)
• Lep­tin may also pro­mote coro­nary artery dis­ease, hyper­ten­sion, & throm­bo­sis (27; 28) and has been linked to lev­els of C-reactive pro­tein, a well-studied marker of inflam­ma­tion related to car­dio­vas­cu­lar dis­ease (29).
• Lep­tin may have mod­u­lat­ing effect on bone (30; 31).
• Lep­tin may help restore hypothalamic-pituitary axes includ­ing gonadal, thy­roid, growth hor­mone, and to a lesser extent adrenal axes (32).

Lep­tin Resistance

Sim­i­lar to insulin resis­tance, lep­tin resis­tance can occur when recep­tors become unre­spon­sive to increas­ing lev­els of lep­tin hor­mone, com­monly found in states of obe­sity & related com­pli­ca­tions such as non-alcoholic fatty liver disease.

There gen­er­ally seems to be a push-pull rela­tion­ship between obe­sity and lep­tin resis­tance with con­fu­sion over whether one causes the other (33).

What is Lep­tin Resistance?

1.) Ele­vated triglyc­erides seem to be an impor­tant medi­a­tor for lep­tin in both obese and star­va­tion states (34; 35), may account for the inflam­ma­tion and immune acti­va­tion that may link obe­sity with lep­tin resis­tance (36), and can be an early sign of insulin resis­tance and poor sugar management.

2.) Lep­tin resis­tance may be caused by altered lep­tin trans­port past the blood brain bar­rier and mal­func­tion­ing of lep­tin recep­tors due to cel­lu­lar stress com­mon in states of obe­sity and insulin resis­tance (37).

3.) Healthy diges­tive and gut func­tion may also be linked to lep­tin resistance

a. Exter­nal tox­ins and inflam­ma­tory food pro­teins such as dietary lectins found in cereal grains (wheat, rice, corn, etc) may dis­rupt the blood brain bar­rier, poten­tially link­ing gut health with lep­tin insensitivity.

b. Lipopolysac­cha­rides (LPS) are inter­nal tox­ins gen­er­ated from imbal­ance of healthy bac­te­ria in the gut and are also asso­ci­ated with the devel­op­ment of lep­tin resis­tance (38)

c. Short chain fatty acids (byprod­ucts of fer­men­ta­tion from healthy bac­te­ria in the colon) can pro­mote lep­tin lev­els to induce sati­ety and may also have anti-inflammatory effects (39)

Med­ical Approach to Lep­tin Resis­tance

I am for­merly trained as a Chi­ro­prac­tor and can­not give advice for or against use of med­ica­tions and am ill-suited to fully review med­ical approaches. Here I am sim­ply review­ing some pieces of infor­ma­tion I came across in my lep­tin research.

1.) Bariatric surgery most effec­tive for pedi­atric obe­sity pos­si­bly through an effect on lep­tin and eat­ing behav­ior, yet comes with poten­tial risks and reserved for most sig­nif­i­cant com­pli­ca­tions of obe­sity (40)

2.) Statins have been shown to mod­u­late lep­tin activ­ity (41), but an ear­lier meta-analysis of ran­dom­ized con­trolled tri­als pub­lished in The Lancet indi­cated a 9% increase in dia­betes inci­dence for those tak­ing statins over a four year period (42). There is a call for more research to clar­ify the role of statins in car­bo­hy­drate metabolism

3.) In stud­ies of rats, Met­formin may help restore lep­tin sen­si­tiv­ity, and may be a use­ful along­side lep­tin in treat­ment of obe­sity (43)

In my opin­ion, obe­sity med­ica­tions are largely unproven, and mostly tar­get the effects of obe­sity such as hypertension.

Med­ica­tions may offer assis­tance in com­bi­na­tion with other approaches, but I feel that they can shift focus away from ubiq­ui­tous lifestyle fac­tors such as:

• high avail­abil­ity of foods high in sugar, fat and salt
• inci­dence of food mar­ket­ing (espe­cially that which tar­gets children)
• pos­si­ble sen­sual cues like sight, and smell that may also trig­ger overeat­ing behavior.

My opin­ion aside, it is impor­tant to work with a health pro­fes­sional to pri­or­i­tize an approach that is right for you.

Food Pol­i­tics and Food Addiction

Food can be highly addic­tive, affect­ing the same brain path­ways as opi­ate drugs!

Our food envi­ron­ment now con­tains food that is cheap, highly palat­able, widely avail­able, and increas­ingly accepted as addictive.

In an arti­cle pub­lished Feb­ru­ary 1st, 2012 in Nature — one of the most highly respected jour­nals on the globe, concludes:

“Added sweet­en­ers pose dan­gers to health that jus­tify con­trol­ling them like alco­hol…” (44)

Mark my words: This may turn out to be one of the most impor­tant jour­nal arti­cles pub­lished in our life­times. We may look back at this arti­cle as one of the most impor­tant devel­op­ments in the fight against obe­sity and related problems.

I rec­om­mend fol­low­ing Mar­ion Nes­tle, PhD, a lead­ing resource in Food Pol­i­tics who has been cov­er­ing the pol­i­tics of obe­sity, food mar­ket­ing to chil­dren, and the sugar debate.

She’s also cov­er­ing the news regard­ing sugar tox­i­c­ity in depth. 

Lep­tin Genes:

Some indi­vid­u­als may be more or less sus­cep­ti­ble to lep­tin resis­tance due to slight dif­fer­ences in gene expression.

For instance, slight dif­fer­ences in lep­tin and lep­tin recep­tor genes known as “poly­mor­phisms” may account for why anti-depressant med­ica­tions may be linked to risk of obe­sity in some peo­ple, and have no asso­ci­a­tion for oth­ers (45).

Ances­tral genes under­ly­ing some of these mech­a­nisms may have devel­oped over mil­lions of years which were crit­i­cal to sur­vival in times of scarce food.

Unfor­tu­nately, now these same genes may now be a trig­ger for obe­sity and related “mod­ern” dis­eases (46).

“Insuf­fi­cient adap­ta­tion” to new envi­ron­men­tal fac­tors such as an increased con­sump­tion of cereal grains from wheat, rice and corn, may partly account for lep­tin resis­tance (47).

Action Steps to Reverse Lep­tin Resis­tance, Improve Eat­ing Behav­ior, & Curb Weight Gain When Diet and Exer­cise Efforts Fail:

1.) Work with a pro­fes­sional trained in func­tional nutri­tion to iden­tify and address imbal­ance of hypothalamus-pituitary path­ways affect­ing reg­u­la­tion of stress, thy­roid func­tion, growth & sex hor­mones.

• Take prac­ti­cal steps to improve sleep such as reduc­ing caf­feine intake.
• High sym­pa­thetic activ­ity and lev­els of cor­ti­sol are related to obe­sity and reduc­ing stress may help mod­u­late lep­tin activ­ity (48; 49; 50).
• I’ve pre­vi­ously writ­ten on herbal approaches to blood sugar man­age­ment and stress relief.
  Take prac­ti­cal steps to improve sleep qual­ity and dura­tion. Sleep loss is asso­ci­ated with low lev­els of lep­tin and pos­si­ble increased risk of obe­sity (51).

2.) Sim­i­larly, iden­tify and address neu­ro­trans­mit­ters imbal­ances such as sero­tonin and dopamine, which can be affected by insulin resistance.

• Work with health pro­fes­sional to assess gas­troin­testi­nal func­tion and bal­ance of healthy bac­te­ria & iden­tify pos­si­ble hid­den infec­tions and food sen­si­tiv­i­ties & intol­er­ances.
• Pay atten­tion to tol­er­ance of dietary lectins found in cereal grains (wheat, rice, corn, etc), pota­toes, toma­toes, pep­pers, and legumes (see list). Dietary lectins may offer a miss­ing link in the case of “dis­eases of afflu­ence” such as obe­sity and type 2 dia­betes. (52).
• Iden­tify high-sensitivity foods such as dairy, soy, eggs, tree nuts, shell­fish, wheat, corn, & other cross-reactive grains.

3.) Take prac­ti­cal steps to imple­ment Med­i­ta­tion and a Low-Palatability Diet as cham­pi­oned by Stephen Guyenet, PhD of Whole Health Source. If you are inter­ested in in-depth analy­sis of this topic, I highly rec­om­mend read­ing Guyenet’s “What Causes Insulin Resis­tance” series.

• Diets high in both fat and fruc­tose are asso­ci­ated with lep­tin resis­tance and can cre­ate a vicious cycle of poor weight man­age­ment (53; 54). This vicious cycle may reflect the “addic­tive” nature of cer­tain foods.
• High sugar, salt, and fat diet may con­tribute to overeat­ing due to addic­tive qual­i­ties and effect on dopamine neu­rons (55; 56; 57; 58)
• Stay away from pizza, ice cream, chips, fried foods, and other fatty, sug­ary, & salty snacks that fit a high-palatability profile
• Do not con­fuse this with fad “low-fat”, “low-carb” and “low-salt” diets.

4.) Mind­ful eat­ing may be impor­tant lifestyle skill to break the cycle of overfeeding.

• Mind­ful eat­ing can be con­sid­ered a form of med­i­ta­tion and is asso­ci­ated with improved sugar con­trol, feed­ing behav­ior, and weight management.
• Telling some­one to eat mind­fully can be imprac­ti­cal due to its demand for con­scious brain resources & it’s dis­re­gard for stress in our lives.
• We love read­ing advice about eat­ing more mind­fully, but we still fail to do actu­ally prac­tice it.

5.) Bal­ance dif­fer­ent forms of exer­cise. A mix of aer­o­bic and anaer­o­bic exer­cise appears to work bet­ter for decreas­ing lep­tin and increas­ing anti-inflammatory hor­mones than either type by itself (59).

• Some evi­dence indi­cates that women may ben­e­fit more from a focus on resis­tance train­ing (de Salles BF, et al. Int J Sports Med. 2010 Jul;31(7):441–50).

6.) Nutraceu­ti­cal “Food as Med­i­cine” approaches:

• Cur­cumin from turmeric shown to down­reg­u­late lep­tin (60)
• Omega 3 fatty acids found in fish, nuts, seeds, and some plants may help mod­u­late release of lep­tin (61)
• Pro­bi­otics may help to improve gas­troin­testi­nal integrity and immune bal­ance, while also improv­ing pro­duc­tion of short chain fatty acids which may have direct influ­ence on lep­tin as men­tioned earlier.
• A host of other com­pounds includ­ing, but not lim­ited to L-glutamine, aloe leaf, licorice extract, vit­a­min D, rose­mary, hops, gin­ger, gar­lic, mono­lau­rin, green tea extract, & more may offer pos­i­tive ben­e­fits on gut bac­te­ria, gut-brain inter­ac­tions and gen­eral immune health.

7.) Rec­om­mended read­ing:

• The End of Overeat­ing by David A Kessler (affil­i­ate, non-affiliate)
• The Blood Sugar Solu­tion by Mark Hyman, MD (affil­i­ate, non-affiliate) [pre-order]